Methods for the esterification of alcohols and compounds useful therefor as potential anticancer agents

ABSTRACT

The invention relates to a method for preparing an ester, by admixing a compound having the structure I or IV:                    
     with a base and an alcohol to produce an ester, wherein the alcohol is a precursor to Taxol and its analogs. The present invention also relates to compounds having the structure I and IV and methods of main them therefor. The invention also relates to the esterification of an alcohol by adding an alkoxide to a compound having the structure, VII:                    
     The invention further relates to compounds having the structure I, IV, and VII and methods of making them therefor. The invention further relates to alcohols, and in particular, alcohols that are synthetic precursors to Taxol and analogs thereof.

This application is a divisional of, and claims the benefit of,application Ser. No. 08/989,590, filed Dec. 12, 1997, U.S. Pat. No.6,150,537, which application is hereby incorporated herein by thisreference.

ACKNOWLEDGEMENTS

This invention was made with government support under grants A128731-07and A131827-05 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The invention relates to methods for esterifying alcohols. Inparticular, the invention provides novel compounds and methods useful inthe production of Taxol and Taxol analogs.

BACKGROUND OF THE INVENTION

The esterification of alcohols is a common reaction in organicsynthesis. Once the ester is produced, the ester can undergo furtherreactions to produce complex molecules. This approach is especiallysignificant in the synthesis of natural products and non-naturalsynthetic compounds that exhibit biological activity. By converting ahydroxyl group to an ester, the chemical properties of the compound canchange dramatically. An example of this improved property is theanti-cancer drug, Taxol.

Taxol and other antitumor taxoids constitute some of the most importantdiscoveries in cancer chemotherapy in recent years. Taxol and Taxotere,which is a semi-synthetic analog of Taxol, have been approved by the FDAfor the treatment of advanced ovarian and breast cancer. AdditionallyTaxol and Taxotere may be useful for the treatment of non-small-celllung cancer, head and neck cancer and several other cancers. Thestructures of Taxol and Taxotere are shown below.

Taxol and Taxotere differ in their structure at the C-10 and C-3′positions. While Taxol was first isolated from the bark of the pacificyew tree, Taxus brevifola, Taxotere, a synthetic analog of Taxol,possesses better bioavailability than Taxol. Due to the limitedavailability of Taxol from the yew tree (1 Kg from 10000 Kg of bark),different strategies including total synthesis, semisynthesis, cell andtissue culture of taxus spp., have been investigated so that largeamounts of Taxol can be produced. Although the total synthesis of Taxolwas accomplished in 1994, lengthy multi-step sequences led to pooroverall yield of Taxol. Therefore, total synthesis has not to date beena viable alternative to solve the supply problem.

One approach to a large scale production of Taxol and Taxotere is theirsemisynthesis from 10-deacetyl baccatin III (referred to as baccatin IIIor baccatin), shown below. Baccatin III can be readily obtained from theneedles of the yew tree Taxus baccata. Importantly, yew needles can bequickly regenerated; therefore, a continuous supply of Taxol may beavailable without affecting the yew population.

Structure-activity relationships of Taxol derivatives indicate that theC-13 N-benzoyl-3-phenyl isoserine side chain, with the 2′R, 3′Sstereochemistry, is of crucial importance for Taxol's cytotoxicity.Although there are methods in the art for the asymmetric synthesis ofthe C-13 side chain, coupling the side chain to the C-13 hydroxyl groupis not a simple endeavor. The coupling reaction is complicated by thefact that the C-13 hydroxyl group is situated in the skeletal concavityof baccatin III, which makes this hydroxyl group sterically hindered.Furthermore, the C-13 hydroxyl group has been proposed to form astabilizing hydrogen bond with the C-4 acetate moiety. These two factorscontribute to the difficulty encountered in attaching the side chain tothe C-13 hydroxyl group.

One approach to attaching the isoserine side chain to the C-13-hydroxylgroup involves a condensation reaction between baccatin and an isoserineacid. Greene et al. (J. Am. Chem. Soc. 1988, 110, 5917) discloses thedirect esterification reaction of a protected form of baccatin III andan isoserine acid under vigorous conditions (73° C. for 4 days).International Patent Application No. WO 94/18186 to Swindell et al.;U.S. Pat. No. 5,675,025 to Sisti et al.; and U.S. Pat. No. 5,597,931 toDanishefsky et al. also disclose the condensation reaction betweenprotected baccatins and isoserine acids and esters.

Another approach involves the condensation reaction between aheterocycle containing a carboxylic acid group and baccatin, followed bytreatment with an acid to open the ring and produce the side chain atC-13. Kingston et al. (Tetrahedron Letters 1994, vol 35, no. 26, pp4483) and International Patent Application No. WO 97/00870 to Gennari etal. disclose the coupling of oxazolidines and baccatin via acondensation reaction. U.S. Pat. No. 5,599,942 to Bouchard et al.;International Patent Application No. WO 94/10169 to Denis et al.;International Patent Application No. WO 94/10169; and Kanazawa et al.(J. Chem. Chem. Com. 1994, 2591) disclose the coupling of a 1,3-oxazolewith baccatin followed by acid hydrolysis produced Taxol and derivativesthereof. In the respective condensation reactions disclosed in theabove-identified patents and articles, the stereochemistry at C-2 of theheterocycle, wherein C-2 is the carbon bonded to the carboxylic acidgroup, has to be established (either S or R stereochemistry).

Gennari et al. (Angew. Chem. Int. Ed. Engl. 1996, 35, 1723) disclosesthe reaction between a protected baccatin and a thioester of anoxazolidine in the presence of a base. In the case of the oxazolidine,seven steps were required to produce the oxazolidine with the thioestergroup, wherein the first step involves the use of chiral boron agent.The resulting oxazolidine thioester produced and subsequently coupledwith baccatin is the anti isomer and not the syn isomer. The couplingreaction involves adding a base to a mixture of the protected baccatinand the oxazolidine thioester. An excess of oxazolidine thioester (3.5equivalents) and base (4.5 equivalents) are used in the couplingreaction. Similar to the condensation reactions described above, thestereochemistry at C-2 of the oxazolidine thioester is also established.

Therefore, there remains a need for a more efficient, high yieldsynthesis of Taxol and other similar compounds. In addition, thereexists a need for synthetic methods where the stereochemistry at C2 ofthe precursor to the side chain does not have to be established.

SUMMARY OF THE INVENTION

To overcome the shortcomings described above, the present invention, inone aspect, relates to a method for preparing an ester, comprising:

(a) admixing a compound having the structure I:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl; or substituted or unsubstituted aryl; and

X is a halogen or OR₃, wherein R₃, is from C₁ to C₁₂ branched orstraight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl,or S(O)₂R₄₁, wherein R₄₁ is C₁ to C₁₂ branched or straight chain alkyl;or substituted or unsubstituted aryl,

with a base to form an intermediate; and

(b) admixing the intermediate of step (a) with an alcohol, an alkoxide,or a combination thereof.

The invention further relates to a method for preparing an ester,comprising admixing a compound having the structure III:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl,

with an alcohol, an alkoxide or a combination thereof.

The invention further relates to a method for preparing an ester,comprising admixing:

(a) a base;

(b) an alcohol, an alkoxide or a combination thereof; and

(c) a compound having the structure I:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl; or substituted or unsubstituted aryl; and

X is a halogen or OR₃, wherein R₃ is from C₁ to C₁₂ branched or straightchain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, S(O)₂R₄₁,wherein R₄₁ is C₁ to C₁₂ branched or straight chain alkyl; orsubstituted or unsubstituted aryl.

The invention further relates to a method for preparing an ester,comprising admixing:

(a) a base;

(b) an alcohol, an alkoxide or a combination thereof; and

(c) a compound having the structure IV:

wherein,

R₉ and R₁₀ are, independently, an aralkyl or C(O)R₃₁, wherein R₃₁ is C₁to C₁₂ straight chain or branched alkyl; substituted or unsubstitutedaryl; or aralkyl;

R₁₁ is from C₁ to C₁₂ branched or straight chain alkyl or substituted orunsubstituted aryl;

R₁₂ is silyl, alkyl, acyl, aryl, or aralkyl; and

Y is a halogen or OR₁₃, wherein R₁₃ is from C₁ to C₁₂ branched orstraight chain alkyl; or substituted or unsubstituted aryl; aralkyl;acyl; or S(O)₂R₄₂, wherein R₄₂ is C₁ to C₁₂ straight chain or branchedalkyl; or substituted or unsubstituted aryl.

The invention further relates to a method for preparing an ester,comprising admixing:

(a) an alcohol, an alkoxide, or a combination thereof; and

(b) a compound having the structure V:

wherein,

R₉ and R₁₀ are, independently, an aralkyl or C(O)R₃₁, wherein R₃₁ is C₁to C₁₂ straight chain or branched alkyl; substituted or unsubstitutedaryl; or aralkyl;

R₁₁ is from C₁ to C₁₂ branched or straight chain alkyl or substituted orunsubstituted aryl; and

R₁₂ is silyl, alkyl, aryl, aralkyl or acyl.

The invention further relates to a method for preparing a compoundhaving the structure I:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl; and

X is OR₃, wherein R₃ is from C₁ to C₁₂ branched or straight chain alkyl;substituted or unsubstituted aryl; aralkyl; acyl, or S(O)₂R₄₁, whereinR₄₁ is C₁ to C₁₂ branched or straight chain alkyl; or substituted orunsubstituted aryl, and

R₂ and C(O)X are cis to one another,

comprising:

(a) admixing a compound having the structure VI:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl;

X is OR₃, wherein R₃ is from C₁ to C₁₂ branched or straight chain alkyl;substituted or unsubstituted aryl; aralkyl; acyl, or S(O)₂R₄₁, whereinR₄₁ is C₁ to C₁₂ branched or straight chain alkyl; or substituted orunsubstituted aryl; and

the hydroxyl group and amide group are cis to one another,

with a cyclization agent.

The invention further relates to a compound having the formula I:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl;

X is OR₃, wherein R₃ is halogen; C₁ to C₁₂ branched or straight chainalkyl; substituted or unsubstituted aryl; aralkyl; acyl, aralkyl, orS(O)₂R₄₁, wherein R₄₁ is C₁ to C₁₂ branched or straight chain alkyl; orsubstituted or unsubstituted aryl; and

R₂ and C(O)X are cis to one another.

The invention further relates to a compound having the structure IV:

wherein,

R₉ and R₁₀ are aralkyl;

R₁₁ is substituted or unsubstituted aryl;

R₁₂ is acyl, silyl, alkyl, aryl or aralkyl; and

Y is a halogen or OR₁₃, wherein R₁₃ is from C₁ to C₁₂ branched orstraight chain alkyl; substituted or unsubstituted aryl, acyl, aralkylor S(O)₂R₄₂, wherein R₄₂ is C₁ to C₁₂ branched or straight chain alkyl;or substituted or unsubstituted aryl.

The invention further relates to a method for preparing a compoundhaving the structure IV:

wherein,

R₉ and R₁₀ are aralkyl;

R₁₁ is substituted or unsubstituted aryl;

R₁₂ is acyl, silyl, alkyl, aryl, or aralkyl; and

Y is OR₁₃, wherein R₁₃ is from C₁ to C₁₂ branched or straight chainalkyl; substituted or unsubstituted aryl; acyl, aralkyl, or S(O)₂R₄₂,wherein R₄₂ is C₁ to C₁₂ branched or straight chain alkyl or substitutedor unsubstituted aryl,

comprising:

(a) admixing abase and a compound having the structure IX:

wherein,

R₉ and R₁₀ are aralkyl;

R₁₁ is substituted or unsubstituted aryl; and

Y is OR₁₃, wherein R₁₃ is from C₁ to C₁₂ branched or straight chainalkyl; or substituted or unsubstituted aryl, acyl, aralkyl, or

S(O)₂R₄₂, wherein R₄₂ is C₁ to C₁₂ branched or straight chain alkyl; orsubstituted or unsubstituted aryl,

to produce an intermediate, and

(b) admixing the intermediate of step (a) with an esterification agent,a silylating agent, or an alkylating agent.

The invention further relates to a method for preparing an ester,comprising admixing a compound having the structure VII:

wherein,

R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)R₂₂, whereineach R₂₁ is, independently, branched or straight chain C₁-C₁₂ alkyl; andR₂₂ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₇ is substituted or unsubstituted aryl, aralkyl, or from C₁-C₁₂branched or straight chain alkyl;

R₁₈ is hydrogen; branched or straight chain C₁-C₁₂ alkyl; unsubstitutedor substituted aryl; aralkyl; Si(R₂₈)₃ or C(O)R₂₉, wherein, each R₂₈ is,independently, branched or straight chain C₁-C₁₂ alkyl; or aralkyl;

R₂₉ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₉ and R₂₀ are, independently, branched or straight chain C₁-C₁₂ alkyl,aryl, aralkyl, or C(O)OR₃₀, wherein R₁₉ is not hydrogen;

R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and

V and W are, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ ishydrogen; branched or straight chain C₁-C₁₂ alkyl; or aralkyl,

with an alkoxide.

The invention further relates to a method for preparing a compoundhaving the structure VII:

wherein,

R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)R₂₂, whereineach R₂₁ is, independently, branched or straight chain C₁-C₁₂ alkyl; andR₂₂ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₇ is substituted or unsubstituted aryl, aralkyl, or from C₁-C₁₂branched or straight chain alkyl;

R₁₈ is branched or straight chain C₁-C₁₂ alkyl; unsubstituted orsubstituted aryl; aralkyl; Si(R₂₈)₃ or C(O)R₂₉, wherein,

each R₂₈ is, independently, branched or straight chain C₁-C₁₂ alkyl; oraralkyl;

R₂₉ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₉ and R₂₀ are, independently, branched or straight chain C₁-C₁₂ alkyl,aryl, aralkyl, or C(O)OR₃₀, wherein R₁₉ is not hydrogen;

R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and

V and W are, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ ishydrogen; branched or straight chain C₁-C₁₂ alkyl; or aralkyl,

comprising,

(a) admixing

(i) a compound having the structure X

wherein R₁₈-R₂₀ are as above,

(ii) a Lewis acid; and

(iii) a base,

to produce a first intermediate;

(b) reacting the first intermediate of step (a) with a compound havingthe structure XI:

wherein R₁₅ and R₁₇ are as above,

to produce a second intermediate; and

(c) admixing the second intermediate of step (b) with a proton source.

The invention further relates to a compound having the structure VII:

wherein,

R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)R₂₂, whereineach R₂₁ is, independently, branched or straight chain C₁-C₁₂ alkyl; andR₂₂ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₇ is substituted or unsubstituted aryl, aralkyl, or from C₁-C₁₂branched or straight chain alkyl;

R₁₈ is hydrogen; branched or straight chain C₁-C₁₂ alkyl; unsubstitutedor substituted aryl; aralkyl; Si(R₂₈)₃ or C(O)R₂₉, wherein,

each R₂₈ is, independently, branched or straight chain C₁-C₁₂ alkyl; oraralkyl;

R₂₉ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₉ and R₂₀ are, independently, branched or straight chain C₁-C₁₂ alkyl,aryl, aralkyl, or C(O)OR₃₀, wherein R₁₉ is not hydrogen;

R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and

V and W are, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ ishydrogen; branched or straight chain C₁-C₁₂ alkyl; or aralkyl.

The invention further relates to a method for preparing a compoundhaving the structure VII:

wherein,

R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)OMe, whereineach R₂₁ is, independently, branched or straight chain C₁-C₁₂ alkyl; andR₂₂ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₇ is substituted or unsubstituted aryl, aralkyl, or from C₁-C₁₂branched or straight chain alkyl;

R₁₈ is hydrogen:

R₁₉ and R₂₀ are, independently, branched or straight chain C₁-C₁₂ alkyl,aryl, aralkyl, or C(O)OR₃₀, wherein R₁₉ is not hydrogen;

R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and

V and W are, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ ishydrogen; branched or straight chain C₁-C₁₂ alkyl; or aralkyl,

comprising,

(a) admixing

(i) a compound having the structure XIII

wherein R₁₉-R₂₀ and R₂₂ are as above,

(ii) a Lewis acid; and

(iii) a first base,

to produce a first intermediate;

(b) reacting the first intermediate of step (a) with a compound havingthe structure XI:

wherein R₁₅ and R₁₇ are as above,

to produce a second intermediate; and

(c) admixing the second intermediate with a basic buffer, wherein thebuffer comprises a second base.

The invention further relates a compound having the structure XIV or XV:

wherein,

R₄₄ and R₄₅ are, independently, hydrogen; C₁-C₁₂ branched or straightchain alkyl; or R₄₄ and R₄₅ art part of a cycloaliphatic group;

when g is a single bond, R₄₆ is hydroxy; acetyl; or C₁-C₁₂ branched orstraight chain alkoxy;

when g is a double bond, R₄₆ is oxygen;

R₄₇ is a C₁-C₁₂ branched or straight chain alkyl ester; C₁-C₁₂ branchedor straight chain alkyl; carboalkoxy; hydroxyalkyl; or derivatized orprotected hydroxyalkyl;

R₄₈ is C₁-C₁₂ branched or straight chain alkyl; substituted orunsubstituted aryl; acetyl; hydroxyalkyl; or derivatized or protectedhydroxyalkyl;

R₄₉ and R₅₀ are, independently, hydrogen; C₁-C₁₂ branched or straightchain alkyl or alkoxy; or acetyl, provided that when one of R₄₉ or R₅₀is hydrogen, the other of R₄₉ and R₅₀ is not hydrogen;

when m is a double bond, R₅₁ is oxygen;

when m is a single bond, R₅₁ is OH or OC(O)R₅₂, wherein R₅₂ issubstituted or unsubstituted aryl; or cycloaliphatic; and

the hydroxyl group is located at carbon h or i.

None of the references described above disclose the methods andcompounds of the present invention. Additional advantages of theinvention will be set forth in part in the description which follows,and in part will be obvious from the description, or may be learned bypractice of the invention. The advantages of the invention will berealized and attained by means of the elements and combinationsparticularly pointed out in the appended claims. It is to be understoodthat both the foregoing general description and the following detaileddescription are exemplary and explanatory only and are not restrictiveof the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of preferred embodiments of the inventionand the examples included therein.

Before the present compositions of matter and methods are disclosed anddescribed, it is to be understood that this invention is not limited tospecific synthetic methods or to particular formulations, as such may,of course, vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only andis not intended to be limiting.

In this specification and in the claims which follow, reference will bemade to a number of terms which shall be defined to have the followingmeanings:

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

Throughout the application, the term “compound” refers to all compoundsembodied by the designated structure in the present application. Forexample, compound I refers to all compounds having the structure I asdefined in the application.

The term “aralkyl” is defined as any group that has one or morealiphatic or cycloaliphatic groups attached to an aromatic ring.

The term “cyclization agent” is defined as an agent that activates ahydroxyl group and renders the carbon attached to it more susceptible tointernal nucleophilic attack.

The term “esterification agent” is defined as any agent that willcatalyze the formation of an ester from an alcohol or alkoxide and acarboxylic acid.

Esterification of Alcohols—Part I

In accordance with the purpose(s) of this invention, as embodied andbroadly described herein, this invention, in one aspect, relates to amethod for preparing an ester, comprising:

(a) admixing a compound having the structure I:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl; or substituted or unsubstituted aryl; and

X is a halogen or OR₃, wherein R₃ is from C₁ to C₁₂ branched or straightchain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, orS(O)₂R₄₁, wherein R₄₁ is C₁ to C₁₂ branched or straight chain alkyl; orsubstituted or unsubstituted aryl,

with abase to form an intermediate; and

(b) admixing the intermediate of step (a) with an alcohol, an alkoxide,or a combination thereof.

The invention further relates to a method for preparing an ester,comprising admixing a compound having the structure III:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl,

with an alcohol, an alkoxide or a combination thereof.

The invention further relates to a method for preparing an ester,comprising admixing:

(a) a base;

(b) an alcohol, an alkoxide or a combination thereof; and

(c) a compound having the structure I:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl; or substituted or unsubstituted aryl; and

X is a halogen or OR₃, wherein R₃ is from C₁ to C₁₂ branched or straightchain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, orS(O)₂R₄₁, wherein R₄₁ is C₁ to C₁₂ branched or straight chain alkyl; orsubstituted or unsubstituted aryl.

The invention further relates to a method for preparing an ester,comprising admixing:

(a) a base;

(b) an alcohol, an alkoxide or a combination thereof; and

(c) a compound having the structure IV:

wherein,

R₉ and R₁₀ are, independently, an aralkyl or C(O)R₃₁, wherein R₃₁ is C₁to C₁₂ straight chain or branched alkyl; substituted or unsubstitutedaryl; or aralkyl;

R₁₁ is from C₁ to C₁₂ branched or straight chain alkyl or substituted orunsubstituted aryl;

R₁₂ is silyl, alkyl, acyl, aryl, or aralkyl; and

Y is a halogen or OR₁₃, wherein R₁₃ is from C₁ to C₁₂ branched orstraight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl;or S(O)₂R₄₂, wherein R₄₂ is C₁ to C₁₂ straight chain or branched alkyl;substituted or unsubstituted aryl

The invention further relates to a method for preparing an ester,comprising admixing:

(a) an alcohol, an alkoxide, or a combination thereof; and

(b) a compound having the structure V:

wherein,

R₉ and R₁₀ are, independently, an aralkyl or C(O)R₃₁, wherein R₃₁ is C₁to C₁₂ straight chain or branched alkyl; substituted or unsubstitutedaryl; or aralkyl;

R₁₁ is from C₁ to C₁₂ branched or straight chain alkyl or substituted orunsubstituted aryl; and

R₁₂ is silyl, alkyl, aryl, aralkyl or acyl.

The applicants have discovered that the combination of a base, analcohol, and compound I or IV results in the formation of an ester. Inone embodiment, the base can be added to a mixture of the alcohol andcompound I and IV. In a preferred embodiment, compound I or IV istreated with a base, followed by the addition of the alcohol.

Without wishing to be bound by theory, it is believed that when the baseand compound I or IV are combined together, the ketene complexes III andV are produced, respectively. It is believed that the base deprotonatesa hydrogen at the α-carbon (the carbon adjacent to the C(O)X group) of Iand IV with concomitant loss of the leaving group, X and Y,respectively, to generate the ketene complex. The ketene complexes IIIand V are highly electrophilic; thus, they are susceptible tonucleophilic attack. When a ketene is treated with an alcohol of thepresent invention, the alcohol reacts at C1 of the ketene to produce thecorresponding ester (eq. 1). In another embodiment, an alkoxide willreact with the ketene to generate the ester. In the present invention,the ketene complexes III and V are not isolated, but generated in situprior to the addition of the alcohol.

The bases useful for generating the ketene complexes of the presentinvention include, but are not limited to, an amide, a secondary amineor a tertiary amine. An amide is defined herein as (R)₂N^(⊖), whereineach R is preferably an aliphatic group, a cycloaliphatic group, or asilyl group. Examples of amides useful in the present invention include,but are not limited to, potassium hexamethyldisilazide, sodiumhexamethyldisilazide, lithium diisopropylamide, lithiumhexamethyldisilazide, and lithium 2,2,6,6-tetramethylpiperidine. Anexamples of a secondary amine includes, but is not limited to,2,2,6,6-tetramethylpiperidine. Examples of tertiary amines include, butare not limited to, dimethyl ethyl amine, triethylamine and pyridine.

One advantage of the present invention is that the stereochemistry at C2of compounds I and IV does not have to be set. Thus, the stereochemistryat C2 can be S or R. When I-trans and I-cis are treated with a base(Scheme I), deprotonation at C2 and subsequent loss of X results in theformation of the ketene complex III. Thus, the applicants havediscovered that the cis and trans isomers of I and IV can be used toesterify an alcohol, which is highly desirable and nowhere taught,suggested or otherwise motivated in the art.

Another advantage of the present method is that once the ketenecomplexes III and V are generated, nucleophilic attack by the alcohol oralkoxide can occur diasteroselectively. In one embodiment, in the caseof the acyclic ketene complex V, nucleophilic attack by the alcohol oralkoxide will most likely occur opposite or anti to the adjacent R groupat C_(b) of V. In another embodiment, in the case of the cyclic ketenecomplex III, nucleophilic attack by the alcohol or alkoxide can occuranti or syn to the adjacent R group at C_(a); however, due tothermodynamic considerations, the trans ester is the predominant productformed. Thus, by varying the stereochemistry at C_(a) and C_(b), it ispossible to generate optically active esters using this method of thepresent invention. This feature of the present invention is very usefulwith respect to the synthesis of biologically active compounds thatpossess ester groups.

In one embodiment, a compound having the structure I can be used toesterify an alcohol. In the case of compound I, R₁ and R₂ are,independently, from C₁ to C₁₂ branched or straight chain alkyl orsubstituted or unsubstituted aryl; and X is a halogen or OR₃, wherein R₃is from C₁ to C₁₂ branched or straight chain alkyl; substituted orunsubstituted aryl; aralkyl; acyl, or S(O)₂R₄₁, wherein R₄₁ is C₁ to C₁₂branched or straight chain alkyl or substituted or unsubstituted aryl.Throughout the application, the alkyl group is from C₁ to C₁₂ branchedor straight chain alkyl, preferably from C₁ to C₆ branched or straightchain alkyl, and more preferably from C₁ to C₄ branched or straightchain alkyl. The term “acyl” is defined as a group having the structureR′(O)CO, wherein R′ is alkyl, aryl, or aralkyl. Acyl groups useful inthe present invention include, but are not limited to, acetyl andbenzoyl. The term “aralkyl” is defined as any group that has one or morealiphatic or cycloaliphatic groups attached to an aromatic ring.Examples of an aralkyl group of the present invention include, but arenot limited to, benzyl and p-nitrobenzyl groups. In one embodiment, R₁and R₂ are phenyl; R₃ is methyl; and the stereochemistry at a is S. Inanother embodiment, R₁ and R₂ are phenyl; R₃ is isopropyl; and thestereochemistry at a is S. In yet another embodiment, R₁ and R₂ arephenyl; R₃ is tert-butyl; and the stereochemistry at a is S.

The invention further relates to a method for preparing a compoundhaving the structure I:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl; and

X is OR₃, wherein R₃ is from C₁ to C₁₂ branched or straight chain alkyl;substituted or unsubstituted aryl; aralkyl; acyl, or S(O)₂R₄₁, whereinR₄₁ is C₁ to C₁₂ branched or straight chain alkyl; or substituted orunsubstituted aryl, and

R₂ and C(O)X are cis to one another,

comprising:

(a) admixing a compound having the structure VI:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl;

X is OR₃, wherein R₃ is from C₁ to C₁₂ branched or straight chain alkyl;substituted or unsubstituted aryl; aralkyl; acyl, or S(O)₂R₄₁, whereinR₄₁ is C₁ to C₁₂ branched or straight chain alkyl; or substituted orunsubstituted aryl; and

the hydroxyl group and amide group are cis to one another,

with a cyclization agent.

The applicants have discovered a method for preparing a compound havingthe structure I, wherein R₂ and C(O)X are cis to one another. The cisand trans isomers of compound I are shown in Scheme I. The artheretofore only disclosed a method for making the trans isomer ofcompound I.

The use of a cyclization agent is necessary to cyclize compound VI tocompound I. An example of a cyclization agent useful in the presentinvention is triflic anhydride with pyridine. Experimental conditionsfor the production of I via the cyclization of VI are outlined in theforthcoming examples.

The invention further relates to a compound having the formula I:

wherein,

R₁ and R₂ are, independently, from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl;

X is OR₃, wherein R₃ is halogen; C₁ to C₁₂ branched or straight chainalkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)₂R₄₁,wherein R₄₁ is C₁ to C₁₂ branched or straight chain alkyl; orsubstituted or unsubstituted aryl; and

R₂ and C(O)X are cis to one another.

Compounds having the structure I, wherein the compound is the cisisomer, are not disclosed in the art. In one embodiment, R₁ and R₂ arephenyl; R₃ is methyl; and the stereochemistry at a is S. In anotherembodiment, R₁ and R₂are phenyl; R₃ is tert-butyl; and thestereochemistry at a is S. In another embodiment, R₁ and R₂ are phenyl;R₃ is isopropyl; and the stereochemistry at a is S. In anotherembodiment, R₁ and R₂ are phenyl; R₃ is phenyl; and the stereochemistryat a is S. In another embodiment, R₁ and R₂ are phenyl; R₃ is2,3-dimethyl propyl, wherein the stereochemistry at the 2-position is S;and the stereochemistry at a is S.

In another embodiment, compound IV can be used to esterify an alcohol.In this case, R₉ and R₁₀ are, independently, an aralkyl or C(O)R₃₁,wherein R₃₁ is C₁ to C₁₂ straight chain or branched alkyl; substitutedor unsubstituted aryl; or aralkyl; R₁₁ is from C₁ to C₁₂ branched orstraight chain alkyl or substituted or unsubstituted aryl; R₁₂ is silyl;alkyl; aryl; acyl; or aralkyl; and Y is a halogen or OR₁₃, wherein R₁₃is from C₁ to C₁₂ branched or straight chain alkyl or substituted orunsubstituted aryl, acyl, aralkyl or S(O)₂R₄₂, wherein R₄₂ is C₁ to C₁₂branched or straight chain alkyl or substituted or unsubstituted aryl.In one embodiment, R₉ is benzyl; R₁₀ is α-methyl benzyl; R₁₁ is phenyl;R₁₂ is C(O)Ph; R₁₃ is tert-butyl; and the stereochemistry at b is S. Inanother embodiment, R₉ is benzyl; R₁₀ is α-methyl benzyl; R₁₁ is phenyl;R₁₂ is C(O)Ph; R₁₃ is methyl; and the stereochemistry at b is S. In yetanother embodiment, R₉ is benzyl; R₁₀ is α-methyl benzyl; R₁₁ is phenyl;R₁₂ is C(O)Ph; Y is chloride; and the stereochemistry at b is S. Asdescribed above, the stereochemistry at C2 does not have to be set;therefore, NR₉R₁₀ and OR₁₂ can be syn or anti to one another.

The invention further relates to a method for preparing a compoundhaving the structure IV:

wherein,

R₉ and R₁₀ are aralkyl;

R₁₁ is substituted or unsubstituted aryl;

R₁₂ is acyl, silyl, alkyl, aryl, or aralkyl; and

Y is OR₁₃, wherein R₁₃ is from C₁ to C₁₂ branched or straight chainalkyl or substituted or unsubstituted aryl, acyl, aralkyl or S(O)₂R₄₂,wherein R₄₂ is C₁ to C₁₂ branched or straight chain alkyl or substitutedor unsubstituted aryl,

comprising:

(a) admixing a base and a compound having the structure IX:

wherein,

R₉ and R₁₀ are aralkyl;

R₁₁ is substituted or unsubstituted aryl; and

Y is OR₁₃, wherein R₁₃ is from C₁ to C₁₂ branched or straight chainalkyl; or substituted or unsubstituted aryl, acyl, aralkyl, or S(O)₂R₄₂,wherein R₄₂ is C₁ to C₁₂ branched or straight chain alkyl; orsubstituted or unsubstituted aryl,

to produce an intermediate, and

(b) admixing the intermediate of step (a) with an esterification agent,a silylating agent, or an alkylating agent.

Treatment of compound IX with a base results in deprotonation of thehydroxyl proton to generate the corresponding alkoxide. The alkoxide isreferred to as the intermediate recited above. The alkoxide is notisolated, but subsequently treated with an esterification agent, asilylating agent, or an alkylating agent to produce compound IV. Theterm “esterification agent” is defined as any agent that will react withan alkoxide to produce an ester. Examples of esterification agentsuseful in the present invention include, but are not limited to, organicanhydrides and acyl halides. In one embodiment, the esterification agentis benzoyl chloride.

The base employed is any compound capable of deprotonating a hydroxylgroup. Bases used to generate the ketene compounds III and V, such asamides, secondary and tertiary amines, are suitable for deprotonation ofthe hydroxyl group of IX. In one embodiment, triethyl amine can be usedas the base. The experimental conditions for preparing compound IV arepresented in the forthcoming examples.

The invention further relates to a compound having the structure IV:

wherein,

R₉ and R₁₀ are aralkyl;

R₁₁ is substituted or unsubstituted aryl;

R₁₂ is acyl, silyl, alkyl, aryl or aralkyl; and

Y is a halogen or OR₁₃, wherein R₁₃ is from C₁ to C₁₂ branched orstraight chain alkyl or substituted or unsubstituted aryl, acyl,aralkyl, or S(O)₂R₄₂, wherein R₄₂ is C₁ to C₁₂ branched or straightchain alkyl; or substituted or unsubstituted aryl.

In one embodiment, R₉ is benzyl; R₁₀ is α-methyl benzyl; R₁₁ is phenyl;R₁₂ is C(O)Ph; and Y is tert-butoxy. In another embodiment, R₉ isbenzyl; R₁₀ is α-methyl benzyl; R₁₁ is phenyl; R₁₂ is C(O)Ph; and Y ismethoxy.

Once the ketene complexes III and V have been generated, the addition ofan alcohol or an alkoxide will result in the formation of an ester. Theapplicants have discovered that a wide variety of alcohols can be addedto the ketene compounds III and V to produce the corresponding ester.Alcohols useful in the present invention include, but are not limitedto, aliphatic alcohols, aromatic alcohols, cycloaliphatic alcohols, orheteroaromatic alcohols. In a preferred embodiment, the alcohol is acycloaliphatic alcohol. In another embodiment, the alcohol is(2S)-hydroxy-3-methylbutane.

In another preferred embodiment, the alcohol is a compound having thestructure II:

wherein,

R₄ is acetyl or hydrogen;

R₅ is hydrogen;

R₆ is benzoyl;

R₇ is acetyl; and

R₈ is hydrogen, SiEt₃ or C(O)CH₂CCl₃.

As described above, it is advantageous to efficiently attach a sidechain to the hydroxyl group at the C-13 position of baccatin andderivatives thereof. In one embodiment, for compound II, R₄ and R₅ arehydrogen; R₆ is benzoyl; R₇ is acetyl; and R₈ is hydrogen, SiEt₃ orC(O)CH₂CCl₃. This alcohol is the precursor to taxotere. In anotherembodiment, R₄ and R₇ are acetyl; R₅ is hydrogen; R₆ is benzoyl; and R₈is hydrogen, SiEt₃ or C(O)CH₂CCl₃. This alcohol is the precursor toTaxol.

The invention further relates a compound having the structure XIV or XV:

wherein,

R₄₄ and R₄₅ are, independently, hydrogen; C₁-C₁₂ branched or straightchain alkyl; or R₄₄ and R₄₅ are part of a cycloaliphatic group;

when g is a single bond, R₄₆ is hydroxy; acetyl; or C₁-C₁₂ branched orstraight chain alkoxy;

when g is a double bond, R₄₆ is oxygen;

R₄₇ is a C₁-C₁₂ branched or straight chain alkyl ester; C₁-C₁₂ branchedor straight chain alkyl; carboalkoxy; hydroxyalkyl; or derivatized orprotected hydroxyalkyl;

R₄₈ is C₁-C₁₂ branched or straight chain alkyl; substituted orunsubstituted aryl; acetyl; hydroxyalkyl; or derivatized or protectedhydroxyalkyl;

R₄₉ and R₅₀ are, independently, hydrogen; C₁-C₁₂ branched or straightchain alkyl or alkoxy; or acetyl, provided that when one of R₄₉ or R₅₀is hydrogen, the other of R₄₉ and R₅₀ is not hydrogen;

when m is a double bond, R₅₁ is oxygen;

when m is a single bond, R₅₁ is OH or OC(O)R₅₂, wherein R₅₂ issubstituted or unsubstituted aryl; or cycloaliphatic; and

the hydroxyl group is located at carbon h or i.

Applicants have discovered that compounds having the structure XIV andXV are structurally simplified analogs of Taxol with incorporatedstructural elements of Taxol which can embody Taxol's biologicalactivity. Due to the difficulty in synthesizing Taxol, simplifiedanalogs could be advantageous over semi-synthetic analogs of Taxol. Thehydroxy group can be positioned at either carbon h or i, and thestereochemistry at these positions can be either R or S. In oneembodiment, the hydroxyl group is at carbon h, and the stereochemistryat carbon h is S. In another embodiment, the hydroxyl group is at carbonh, and the stereochemistry at carbon h is R. In another embodiment, thehydroxyl group is at carbon i, and the stereochemistry at carbon i is S.In another embodiment, the hydroxyl group is at carbon i, and thestereochemistry at carbon i is R.

In another embodiment, R₄₄ and R₄₅ of compounds XIV and XV areindependently, hydrogen or methyl, preferably hydrogen and methyl. Inanother embodiment, R₄₄ and R₄₅ are part of a cycloaliphatic group,wherein the cycloaliphatic group can be cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In one embodiment, the cycloaliphatic groupis a cyclopropyl group. In another embodiment, R₄₇ is methyl ester ormethyl. In another embodiment, R₄₈ is hydroxy, ethoxy, propoxy, orderivatized or protected hydroxy. The term “derivatized or protectedhydroxy” refers to hydroxyl group that has been converted to a alkoxygroup, an aryloxy group, an aralkoxy group, an acyloxy group or asilyloxy group. In another embodiment, m is a single bond and R₅₂ isphenyl or cyclohexyl.

In one embodiment, when the compound has the structure XIV, R₄₄ and R₄₅are hydrogen; g is a double bond; R₄₇ is C(O)OMe; the stereochemistry atcarbon p is R; R₄₈ is methyl; the stereochemistry at carbon k is S; R₄₈is methyl; R₄₉ is methyl; the stereochemistry at carbon q is R; R₅₀ ishydrogen; the stereochemistry at carbon r is S; m is a single bond; R₅₁is OC(O)Ph; the stereochemistry at carbon j is R; and the hydroxyl groupis at carbon h or i. In another embodiment, the hydroxyl group is atcarbon h and the stereochemistry at carbon h is R. In anotherembodiment, the hydroxyl group is at carbon h and the stereochemistry atcarbon h is S. In another embodiment, the hydroxyl group is at carbon iand the stereochemistry is S.

In one embodiment, when the compound has the structure XIV, R₄₄ and R₄₅are hydrogen; g is a double bond; R₄₇ is C(O)OMe; the stereochemistry atcarbon p is R; R₄₈ is methyl; the stereochemistry at carbon k is S; R₄₉is methyl; the stereochemistry at carbon q is R; R₅₀ is hydrogen; thestereochemistry at carbon r is S; m is a double bond; and the hydroxylgroup is at carbon h or i. In another embodiment, the hydroxyl group isat carbon h and the stereochemistry at carbon h is R. In anotherembodiment, the hydroxyl group is at carbon h and the stereochemistry atcarbon h is S. In another embodiment, the hydroxyl group is at carbon iand the stereochemistry at carbon i is S.

Procedures for preparing compounds XIV and XV are provided in theforthcoming examples. Using the process of the present invention,compounds XIV and XV can be used to esterify alcohols.

In another embodiment, the corresponding alkoxide of the alcoholsdescribed above will also generate an ester when used in the process ofthe present invention. Any base that is capable of deprotonating ahydroxyl proton to produce the corresponding oxide anion is suitable inthe present invention. Bases useful in the present invention include,but are not limited to, potassium hexamethyldisilazide, sodiumhexamethyldisilazide, triethylamine, lithium diisopropylamide, lithiumhexamethyldisilazide, dimethylethylamine, potassium hydride, sodiumhydride or lithium 2,2,6,6-tetramethylpiperidine.

The present invention also provides a process for the esterification ofan alcohol and/or an alkoxide that does not require the use of harshreaction conditions (i.e. elevated temperature, extended reactionstimes). In one embodiment, the base is initially added to compound I orIV prior to the addition of the alcohol or alkoxide. In one embodiment,the amount of base used is less than the amount of compound I or IV. Ina preferred embodiment, an excess amount of base is used relative to theamount of compound I or IV. In the case of compound I, the amount ofbase employed is from 1 to 10 equivalents, preferably 1 to 1.5equivalents to 1 equivalent compound I. In another embodiment, whencompound IV is used, the amount of base used is from 1 to 10 equivalentsto 1 equivalent of compound IV. A slight excess of base relative tocompounds I and IV is necessary in order to generate the correspondingketene prior to the addition of the alcohol or alkoxide.

The process of the present invention typically involves the use of asolvent system Organic solvents known in the art are useful in thepresent invention. Examples of organic solvents useful in the presentinvention include, but are not limited to, tetrahydrofuran, diethylether, toluene, dimethoxyethane, t-butyl methyl ether, or a mixturethereof.

Reaction temperatures and times can vary when adding the base tocompounds I and IV. In one embodiment, the base is added to compound Ifrom −50° C. to 80° C. In another embodiment, the lower limit of thereaction temperature is −45° C., −40° C., −35° C., −30° C., −25° C.,−20° C., or −15° C., and the upper limit is −5° C., −10° C., −15° C.,−20° C., −25° C., 0° C., 20 ° C., 40 ° C., or 60° C. The base is allowedto react with compound I or IV at from 30 seconds to 3 hours. In anotherembodiment, the lower time limit can be 1, 5, 10, 15 minutes, and theupper limit can be 2 hours, 1 hour, 30 minutes, 15 minutes, 10 minutes,or 5 minutes.

Once the ketene complexes III and V have been generated in situ, analcohol, alkoxide, or a combination thereof is added. The amount of thealcohol or alkoxide can be from 1 to 3 equivalents, preferably from 1 to2 equivalents, and more preferably from 1 to 1.2 equivalents. Thealcohol or alkoxide is allowed to react with the ketene at from 15minutes to 24 hours, preferably from 15 minutes to 2 hours. In anotherembodiment, the lower time limit can be 20, 25, 30, 40 or 50 minutes,and the upper limit can be 1 hour, 45 minutes; 1 hour, 30 minutes; 1hour; or 45 minutes. The temperature at which the alcohol and/oralkoxide can be added to the ketene can be from −50° C. to 23° C. Inanother embodiment, the lower temperature limit can be −45° C., −40° C.,−35° C., −30° C., −25° C. or −20° C.; and the lower limit can be 20° C.,15° C., 10° C., 5° C., 0° C., −5° C., −10° C. or −20° C.

Esterification of Alcohols—Parts II

In accordance with the purpose(s) of this invention, as embodied andbroadly described herein, this invention, in one aspect, relates to amethod for preparing an ester, comprising admixing a compound having thestructure VII:

wherein,

R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)R₂₂, whereineach R₂₁ is, independently, branched or straight chain C₁-C₁₂ alkyl; andR₂₂ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₇ is substituted or unsubstituted aryl, aralkyl, or from C₁-C₁₂branched or straight chain alkyl;

R₁₈ is hydrogen; branched or straight chain C₁-C₁₂ alkyl; unsubstitutedor substituted aryl; aralkyl; Si(R₂₈)₃ or C(O)R₂₉, wherein, each R₂₈ is,independently, branched or straight chain C₁-C₁₂ alkyl; or aralkyl;

R₂₉ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₉ and R₂₀ are, independently, branched or straight chain C₁-C₁₂ alkyl,aryl, aralkyl, or C(O)OR₃₀, wherein R₁₉ is not hydrogen;

R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and

V and W are, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ ishydrogen; branched or straight chain C₁-C₁₂ alkyl; or aralkyl,

with an alkoxide.

The alkoxide is prepared in situ by treating the corresponding alcoholwith a base. Bases useful in generating the alkoxide include, but arenot limited to amides, secondary and tertiary amines. In a preferredembodiment, lithium hexamethyldisilazide, sodium hexamethyldisilazide,potassium hexamethyldisilazide, n-butyllithium, sodium hydride,potassium hydride or lithium diisopropylamide can be used. Once thealkoxide is produced, it can react with compound VII to generate anester. Nucleophilic attack at the carbamide followed by the loss of theheterocyclic ring results in the formation of the ester.

The method of the present invention has a number of advantages. First,by varying the stereochemistry of R₁₉ and R₂₀ of compound VII, it ispossible to control the diasteroselectivity of the condensation reactionbetween the alkoxide and compound VII. Second, by varying V and W ofcompound VII, it is possible to enhance or increase the reaction betweenthe alkoxide and compound VII. In one embodiment, V and W are sulfur. Inanother embodiment, R₁₇ is phenyl and R₁₈ is benzoyl. Finally, it ispossible to recover the oxazolidine ring and reuse it after thecondensation reaction.

All of the alcohols described above can be converted to thecorresponding alkoxide and used in the present invention. In oneembodiment, the alkoxide is a compound having the structure VIII:

wherein,

R₂₃ is acetyl or hydrogen;

R₂₄ is hydrogen;

R₂₅ is benzoyl;

R₂₆ is acetyl; and

R₂₇ is hydrogen, SiEt₃ or C(O)CH₂CCl₃.

As described above, an efficient method for attaching a side chain atthe C-13 position of baccatin or derivatives thereof is not known in theart; thus, the applicants have discovered another method for attaching aside chain to precursors of taxol and derivatives thereof. In oneembodiment, for compound VIII, R₂₃ and R₂₄ are hydrogen; R₂₅ is benzoyl;R₂₆ is acetyl; and R₂₇ is hydrogen, SiEt₃ or C(O)CH₂CCl₃. This alkoxideis the precursor to taxotere. In another embodiment, R₂₃ and R₂₆ areacetyl; R₂₄ is hydrogen; R₂₅ is benzoyl; and R₂₇ is hydrogen, SiEt₃ orC(O)CH₂CCl₃. This alkoxide is a precursor to Taxol.

In another embodiment, the alkoxide is a compound having the structureXVI or XVII:

wherein,

R₄₄ and R₄₅ are, independently, hydrogen; C₁-C₁₂ branched or straightchain alkyl; or R₄₄ and R₄₅ are part of a cycloaliphatic group;

when g is a single bond, R₄₆ is hydroxy; acetyl; or C₁-C₁₂ branched orstraight chain alkoxy;

when g is a double bond, R₄₆ is oxygen;

R₄₇ is a C₁-C₁₂ branched or straight chain alkyl ester; C₁-C₁₂ branchedor straight chain alkyl; carboalkoxy; hydroxyalkyl; or derivatized orprotected hydroxyalkyl;

R₄₈ is C₁-C₁₂ branched or straight chain alkyl; substituted orunsubstituted aryl; acetyl; hydroxyalkyl; or derivatized or protectedhydroxyalkyl;

R₄₉ and R₅₀ are, independently, hydrogen; C₁-C₁₂ branched or straightchain alkyl or alkoxy; or acetyl, provided that when one of R₄₉ or R₅₀is hydrogen, then the other of R₄₉ and R₅₀ is not hydrogen;

when m is a double bond, R₅₁ is oxygen;

when m is a single bond, R₅₁ is OC(O)R₅₂, wherein R₅₂ is substituted orunsubstituted aryl; or cycloaliphatic; and

the hydroxyl group is located at carbon h or i.

The invention further relates to a compound having the structure VII:

wherein,

R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)R₂₂, whereineach R₂₁ is, independently, branched or straight chain C₁-C₁₂ alkyl; andR₂₂ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₇ is substituted or unsubstituted aryl, aralkyl, or from C₁-C₁₂branched or straight chain alkyl;

R₁₈ is hydrogen; branched or straight chain C₁-C₁₂ alkyl; unsubstitutedor substituted aryl; aralkyl; Si(R₂₈)₃ or C(O)R₂₉, wherein,

each R₂₈ is, independently, branched or straight chain C₁-C₁₂ alkyl; oraralkyl;

R₂₉ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₉ and R₂₀ are, independently, branched or straight chain C₁-C₁₂ alkyl,aryl, aralkyl, or C(O)OR₃₀, wherein R₁₉ is not hydrogen;

R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and

V and W are, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ ishydrogen; branched or straight chain C₁-C₁₂ alkyl; or aralkyl.

The invention further relates to a method for preparing a compoundhaving the structure VII:

wherein,

R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)R₂₂, whereineach R₂₁ is, independently, branched or straight chain C₁-C₁₂ alkyl; andR₂₂ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₇ is substituted or unsubstituted aryl, aralkyl, or from C₁-C₁₂branched or straight chain alkyl;

R₁₈ is branched or straight chain C₁-C₁₂ alkyl; unsubstituted orsubstituted aryl; aralkyl; Si(R₂₈)₃ or C(O)R₂₉, wherein,

each R₂₈ is, independently, branched or straight chain C₁-C₁₂ alkyl; oraralkyl;

R₂₉ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₉ and R₂₀ are, independently, branched or straight chain C₁-C₁₂ alkyl,aryl, aralkyl, or C(O)OR₃₀, wherein R₁₉ is not hydrogen;

R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and

V and W are, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ ishydrogen; branched or straight chain C₁-C₁₂ alkyl; or aralkyl,

comprising,

(a) admixing

(i) a compound having the structure X

wherein R₁₈-R₂₀ are as above,

(ii) a Lewis acid; and

(iii) a base,

to produce a first intermediate;

(b) reacting the first intermediate of step (a) with a compound havingthe structure XI:

wherein R₁₅ and R₁₇ are as above,

to produce a second intermediate; and

(c) admixing the second intermediate of step (b) with a proton source.

Treatment of compound X with a Lewis acid and a base results in theformation of an enolate, which is the first intermediate recited above.In one embodiment, compound X is treated with the Lewis acid prior tothe addition of the base. Bases useful for generating the enolateinclude, but are not limited to, potassium hexamethydisilazide, sodiumhexamethydisilazide and lithium diisopropylamide. In a preferredembodiment, the base is lithium diisopropylamide. Once the enolate hasbeen prepared in situ, it is treated with the imine compound XI. In apreferred embodiment, R₁₅ of the imine is C(O)Ph. The enolate reactswith the imine to generate a β-amino,α-alkoxyamide, which is the secondintermediate recited above. In another embodiment, the Lewis acidfacilitates the reaction between the enolate and the imine. In oneembodiment, the Lewis acid is a zinc, magnesium, aluminum, boron, tin ortitanium compound. In another embodiment, the Lewis acid comprises adialkylboron triflate, stannous triflate, stannic chloride, stannouschloride or titanium tetrachloride.

Once the β-amino,α-alkoxyamide is produced, it is quenched with a protonsource. Proton sources useful in the present invention include, but arenot limited to, a weak acid or water.

The invention further relates to a method for preparing a compoundhaving the structure VII:

wherein,

R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)OMe, whereineach R₂₁ is, independently, branched or straight chain C₁-C₁₂ alkyl; andR₂₂ is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂branched or straight chain alkyl;

R₁₇ is substituted or unsubstituted aryl, aralkyl, or from C₁-C₁₂branched or straight chain alkyl;

R₁₈ is hydrogen:

R₁₉ and R₂₀ are, independently, branched or straight chain C₁-C₁₂ alkyl,aryl, aralkyl, or C(O)OR₃₀, wherein R₁₉ is not hydrogen;

R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and

V and W are, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ ishydrogen; branched or straight chain C₁-C₁₂ alkyl; or aralkyl,

comprising,

(a) admixing

(i) a compound having the structure XIII

wherein R₁₉-R₂₀ and R₂₂ are as above,

(ii) a Lewis acid; and

(iii) a first base,

to produce a first intermediate;

(b) reacting the first intermediate of step (a) with a compound havingthe structure XI:

wherein R₁₅ and R₁₇ are as above,

to produce a second intermediate; and

(c) admixing the second intermediate with a basic buffer, wherein thebuffer comprises a second base.

In a similar reaction as described above, the addition of a first base,such as an amide or secondary or tertiary amine, to compound XIIIresults in the formation of an enolate, which is the first intermediaterecited above. Once the enolate has been produced, the imine compound XIis added to produce an β-amino,α-alkoxyamide, which is the secondintermediate. The amide is then treated with a basic buffer to generatecompound VII. In one embodiment, the buffer is an aqueous solution ofNaHCO₃ or a phosphate. Upon treatment of the amide intermediate with thebasic buffer, the C(O)R₂₂ group migrates from oxygen to nitrogen. Themigration of C(O)R₂₂, and in particular, C(O)Ph, from oxygen to nitrogenunder basic conditions is well known in the art.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds claimed herein are made and evaluated, and are intended to bepurely exemplary of the invention and are not intended to limit thescope of what the inventors regard as their invention. Efforts have beenmade to ensure accuracy with respect to numbers (e.g., amounts,temperature, etc.) but some errors and deviations should be accountedfor. Unless indicated otherwise, temperature is in °C. or is at roomtemperature and pressure is at or near atmospheric.

General Procedures

Melting points were determined on a Thomas Hoover capillary meltingpoint apparatus and are uncorrected. IR spectra were obtained on aNicolet Impact 400 FT-IR spectrometer using the OMNIC software package.¹H NMR spectra were recorded at either 300 MHz on a General ElectricQE-300 or at 400 MHz on a Varian-400 spectrometer. ¹³C NMR were recordedat either 75 MHz on a General Electric QE-300 or at 100 MHz on aVarian-400 spectrometer. Unless otherwise stated, spectra were recordedin deuterated chloroform (CDCl₃) with residual chloroform (¹H NMR δ7.26ppm, ¹³C NMR δ77.0 ppm) taken as the internal standard. Elementalanalyses were performed by Atlantic Microlab Inc., P. O. Box 2288,Norcross, Ga. Mass spectra were obtained on either a VG 70-S NierJohnson or a JEOL Mass Spectrometer, purchased through NIH and NSF asshared instruments. Analytical Thin Layer Chromatography (TLC) wasperformed on pre-coated glass backed plates purchased from EM Science(silica gel 60 F₂₅₄; 0.25 mm thickness). Flash chromatography wasperformed with silica gel 60 (230-400 mesh ASTM) from EM Science. Allreactions were performed under a dry argon atmosphere in glassware whichwas flame-dried under vacuum unless otherwise indicated. Solvents weredried using activated 4 Å molecular sieves. Dry solvents were usedunless otherwise indicated. Brine refers to a saturated aqueous solutionof NaCl. Saturated NH₄Cl solution refers to a saturated aqueous solutionof NH₄Cl.

Compound 1 was prepared using a slightly modified version of theprocedure previously reported by Sharpless and co-workers (J. Org. Chem.1994, 59, 5104).

Synthesis of Methyl(4S,5S)-2,4-diphenyl-4,5-dihydro-oxazole-5-carboxylate (or2,4-Diphenyl-4(S),5(S)-dihydro-oxazole-5-carboxylic acid methyl ester)(2)

A three-necked flask was charged with 1 (2.59 g, 8.66 mmol) and dryCH₂Cl₂ (43 mL). The suspension was cooled to −30° C. and pyridine (0.84mL, 10.4 mmol) was added. After stirring for several minutes,trifluoromethanesulfonic anhydride (1.45 mL, 8.6 mmol) was addeddropwise and the reaction mixture was gradually warmed from −30° C. to15° C. with an acetone bath. The reaction flask was then removed fromthe bath and was stirred at room temperature for approximately 4 hours.The reaction mixture was then poured into a saturated NaHCO₃ solution(45 mL) and extracted with CH₂Cl₂ (2×). The organic layers were washedwith brine, dried over MgSO₄, filtered and evaporated. Purification bysilica gel chromatography (9:1 hexanes/ethyl acetate increased to 2:1hexanes/ethyl acetate) yielded 2.11 g (87%) of 2 as a white solid.R_(f)0.43 (4:1 hexanes/ethyl acetate); mp 135° C.; IR (CDCl₃) 3065,3030, 2947, 1756, 1656, 1213, 1065, 700 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)δ8.10 (d, J=7.14 Hz, 2H), 7.50 (m, 3H), 7.27 (m, 5H), 5.74, (d, J=10.8Hz, 1H), 5.38 (d, J=10.8 Hz, 1H), 3.20 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)δ168.3, 164.6, 136.8, 131.8, 128.6, 128.4, 128.3, 128.0, 127.9, 127.6,126.6, 80.9, 73.4, 51.4; HRMS (FAB): Calcd for (M+H) C₁₇H₁₆NO₃,282.1130; Found, 282.1134; EA Calcd for C₁₇H₁₅NO₃: C, 72.57; H, 5.38; N,4.98; Found: C, 72.67; H, 5.44; N, 4.94.

Synthesis of Methyl(4S,5R)-2,4-diphenyl-4,5-dihydro-oxazole-5-carboxylate (or2,4-Diphenyl-4(S),5(R)-dihydro-oxazole-5-carboxylic acid methyl ester)(3)

A 15 mL three-necked flask was charged with 2 (69 mg, 0.24 mmol) and dryTHF (1.3 mL). The colorless solution was cooled to −50° C. and lithiumbis(trimethylsilyl)amide (0.25 mL, 1 M solution in THF, 0.25 mmol) wasadded. The mixture was stirred for 10 minutes during which time a brightyellow color developed. The mixture was cooled to −78° C. and quenchedwith saturated NH₄Cl solution (0.5 mL). The mixture was diluted withethyl acetate and water. The aqueous layer was extracted with ethylacetate (3×). The combined organic layers were washed with brine, driedover MgSO₄, filtered, and evaporated to yield 69 mg (100%) of a mixtureof 3 and 2. Crude ¹H NMR indicated a 2:1 ratio of 3 to 2 respectively.The spectral data obtained for 3 was consistent with previouslypublished data. IR 3065, 3030, 2952, 1756-1735, 1656, 1452, 1069, 695cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ8.10 (d, J=7.0 Hz, 2H),7.43 (m, 8H), 5.45(d, J=6.4 Hz, 1H), 4.93 (d, J=6.4 Hz, 1H),3.87 (s, 3H); HRMS (FAB):Calcd. for (M+Li) C₁₇H₁₅NO₃Li, 288.1212; Found, 288.1222.

Synthesis tert-Butyl(4S,5R)-2,4-diphenyl-4,5-dihydro-oxazole-5-carboxylate (4)

A 25 mL three-necked flask was charged with 2 (51.9 mg, 0.18 mmol) anddry THF (1.0 mL). The solution was cooled to 0° C. and lithiumtert-butoxide (0.22 mL, 1.0 M solution in THF, 0.22 mmol) was added.After stirring for 10 minutes, the ice bath was removed and the reactionwarmed to 25° C. The reaction mixture was then diluted with ethylacetate and water. The aqueous layer was extracted with ethyl acetate(3×). The combined organic layers were washed with brine, dried overMgSO₄, filtered and evaporated to yield 45 mg (77%) of crude 4 which wascontaminated with a trace of 2 and 3. Purification by silica gel columnchromatography yielded pure 4 which was consistent with previouslyreported spectral data for the enantiomer of this compound. ¹H NMR (300MHz, CDCl₃) δ8.10 (d, J=7.2 Hz, 2H), 7.41 (m, 8H), 5.38 (d, J=6.5 Hz,1H), 4.79 (d, J=6.5 Hz, 1H), 1.55 (s, 9H).

Esterification of Isopropanol-Synthesis of(4S,5R)-2,4-Diphenyl-4,5-dihydro-oxazole-5-carboxylic add isopropylester (5)

A 15 mL three-necked flask was charged with 2 (52.9 mg, 0.19 mmol) anddry THF (0.95 mL). The colorless solution was cooled to −50° C. After 15minutes, lithium hexamethyldisilazide (0.22 mL, 1.0 M solution in THF,0.22 mmol) was added and a bright yellow color developed. After 12minutes, neat isopropanol (0.5 mL) was added and the reaction mixturewas warmed gradually to 25° C. over one hour. The reaction mixture wasdiluted with ethyl acetate and water. The aqueous layer was extractedwith ethyl acetate (3×). The combined organic layers were dried overMgSO₄, filtered and evaporated to yield 40.4 mg (69%) of a mixture of 5aand 5b. The ratio of 5b (trans) to 5a (cis) was determined to be 6:1 bycrude ¹H NMR. After purification by silica gel chromatography (5% ethylacetate in hexanes) pure 5b was isolated as a clear oil which laterbecame a white solid. R_(f)0.47 (4:1 hexanes/ethyl acetate); IR (CDCl₃)2983, 2933, 1749, 1654, 1062 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ8.11 (m,2H), 7.43 (m, 8H), 5.41 (d, J=6.6 Hz, 1H), 5.20 (m, 1H), 4.86 (d, J=6.6Hz, 1H), 1.33 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ169.6, 164.1, 141.2,131.9, 128.8, 128.7, 128.4, 128.0, 126.8, 126.5, 83.2, 74.7, 69.6, 21.7;HRMS (FAB): Calcd for (M+Li) C₁₉H₁₉NO₃Li, 316.1525; Found, 316.1519.

Using the procedure described above, t-butanol and(2S)-hydroxy-3-methylbutane were esterified as well.

Synthesis oftert-Butyl-(2S,3S,αS)-3-[N-benzyl-N-(α-methylbenzyl)amino]-2-hydroxy-3-phenylpropionate (6)

Compound 6 was prepared according to the literature procedure previouslyreported by Davies and co-workers (Bunnage et al., J. Chem. Soc. PerkinTrans. I, 1994, 2385). The spectral data below is consistent with thedata for the enantiomer of 6 reported in the literature. IR (CDCl₃)3495, 3023, 2977, 1724, 1494, 1454, 1369, 1112, 700 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ7.52 (d, J=7.5 Hz, 4H), 7.31 (m, 11H), 4.43 (bs, 1H), 4.25(m, 2H), 4.16, 3.86 (ABq, J=15.0 Hz, 2H), 2.83 (bs, 1H), 1.24 (d,obscured, 3H), 1.23 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ172.0, 144.0,141.8, 138.2, 129.8, 128.2, 128.0, 127.95, 127.91, 127.5, 126.8, 126.6,82.0, 73.3, 65.5, 57.2, 52.2, 27.6, 14.1; HRMS (FAB): Calcd for (M+Li)C₂₈H₃₃NO₃Li, 438.2620; Found, 438.2639.

Synthesis oftert-Butyl-(2S,3S,αS)-3-[N-benzyl-N-(α-methylbenzyl)amino]-2-benzoyl-oxy-3-phenylpropionate(7)

A 25 mL flask was charged with 6 (149.7 mg, 0.34 mmol). Drytriethylamine (0.1 mL, 0.71 mmol) and CH₂Cl₂ (1 mL) were added and thecolorless solution was cooled to 0° C. Benzoyl chloride (40 μL, 0.34mmol) was added and the reaction was gradually warmed to 25° C. Afterapproximately 2 hours, 4-dimethylaminopyridine (49 mg, 0.40 mmol) wasadded along with an additional 40 μL of benzoyl chloride and 0.5 mL ofCH₂Cl₂. (It was later discovered that 0.5 equivalents of DMAP and 1equivalent of benzoyl chloride was sufficient to drive the reaction tocompletion in about 15 minutes.) After one hour the solvent wasevaporated and the residue was partitioned between ether (6 mL) andwater (6 mL). The mixture was extracted with ether (3×) and the organiclayer was dried with MgSO₄, filtered, and evaporated. The crude productwas a yellow oil contaminated with white crystals (benzoic acid) whichwere further precipitated with hexanes and filtered from the crudeproduct. Purification of crude 7 by silica gel column chromatography (5%ethyl acetate in hexanes) yielded 148 mg (81%) of pure 7 as a clear oil.R_(f)0.60 (4:1 hexanes/ethyl acetate); IR (CDCl₃) 3024, 2977, 1727broad, 1452, 1274, 1110, 700 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ8.04 (d,J=7.3 Hz, 2H), 7.73 (d, J=7.3 Hz, 2H), 7.36 (m, 16H), 5.69 (d, J=3.9 Hz,1H), 4.67 (d, J=3.9 Hz, 1H), 4.25 (q, J=6.7 Hz, 1H), 4.02 (m, 2H), 1.29(d, J=6.7 Hz, 3H), 1.22 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ167.5, 165.5,143.9, 141.5, 138.2, 132.9, 129.8, 129.7, 129.6, 128.2, 128.1, 128.0,127.9, 127.7, 127.6, 126.9, 126.3, 81.9, 73.6, 63.9, 58.4, 52.2, 27.5,15.9; HRMS (FAB): Calcd for (M+Li) C₃₅H₃₇NO₄Li, 542.2883; Found,542.2902.

Synthesis of(2S,3S,αS)-3-[N-Benzyl-N-(α-methylbenzyl)amino]-2-benzoyl-oxy-3-phenyl-propionicacid (8)

A 100 mL flask was charged with 7 (137 mg, 0.25 mmol) and dry CH₂Cl₂(2.5 mL). Trifluoroacetic acid (0.8 mL) was added and the colorlesssolution was stirred at 25° C. for 3.5 hours. The reaction was quenchedwith several milliliters of a saturated NaHCO₃ solution and extractedwith CH₂Cl₂ (3×). The organic layer was dried over MgSO₄, filtered, andevaporated. Purification by silica gel chromatography (4:1 hexanes/ethylacetate increased to 1:1 hexanes/ethyl acetate) yielded 82 mg (68%) of 7as a pure white foam. R_(f) 0.06 (4:1 hexanes/ethyl acetate); IR (CDCl₃)3031, 2930, 1726, 1269, 1113 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ12.63 (bs,1H), 7.71 (d, J=7.4 Hz, 2H), 7.38 (m, 18H), 5.97 (d, J=9.8Hz, 1H), 4.88(d, J=9.8 Hz, 1H), 4.34 (m, 2H), 3.90 (d, 13.8 Hz, 1H), 1.37 (d, J=6.8Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ171.0, 165.2, 138.0, 134.1, 133.1,132.6, 129.7, 129.6, 129.4, 129.1, 129.0, 128.9, 128.5, 128.4, 128.1,68.4, 62.8, 60.1, 51.8, 14.7.

Synthesis ofMethyl-(2S,3S,αS)-3-[N-benzyl-N-(α-methylbenzyl)amino]-2-benzoyl-oxy-3-phenylpropionate(9)

A 10 mL flask was charged with a 40% aqueous potassium hydroxidesolution (0.9 mL) and dry ether (2 mL). While stirring with a teflonstirbar, nitrosomethyl urea (NMU) (103 mg, 1 mmol) was added. Afterstirring for 10 minutes open to the atmosphere, the yellow ether layercontaining diazomethane was pipetted into a vial charged with one KOHpellet as a desiccant. A separate flask was charged with 8 (82 mg, 0.17mmol) and dry ether (1 mL). After 30 minutes, the diazomethane ethersolution was carefully pipetted into the clear solution of 8. The clearreaction mixture stirred for 20 minutes at 25° C. open to theatmosphere. The reaction was monitored by TLC (4:1 hexanes/ethylacetate) and had not gone to completion. Therefore, another identicalbatch of diazomethane was prepared exactly as described above and addeddropwise to the clear reaction mixture until a yellow color persisted,indicating that the reaction was complete. The reaction mixture and anyremaining excess diazomethane were quenched with acetic acid (2 dropsfor the reaction mixture). The reaction mixture was extracted with ether(2×). The ether layer was dried over MgSO₄, filtered and evaporated toyield 71.6 mg (85%) of pure 9 as a white solid. R_(f) 0.47 (4:1hexanes/ethyl acetate); IR (CDCl₃) 3064, 3028, 2952, 1752, 1724, 1276,1116, 904, 736 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.80 (d, J=7.7 Hz, 2H),7.36 (m, 18H), 5.67 (d, J=6.2 Hz, 1H), 4.60 (d, J=6.2 Hz, 1H), 4.18 (q,J=6.7 Hz, 1H), 4.06, 3.85 (ABq, J=14.5 Hz, 2H), 3.56 (s, 3H), 1.19 (d,J=6.8 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ169.2, 165.4, 143.6, 140.4,137.9, 133.1, 129.7, 129.3, 128.3, 128.2, 128.1, 127.9, 127.8, 126.9,126.7, 73.2, 63.8, 57.2, 52.1, 51.9, 14.3; HRMS (FAB): Calcd for (M+Li)C₃₂H₃₁NO₄Li, 500.2413; Found, 500.2426.

Synthesis of(2S,3S,αS)-3-[N-benzyl-N-(α-methylbenzyl)amino]-2-benzoyl-oxy-3-phenyl-propionicanhydride (10)

A 15 mL three-necked flask was charged with p-toluenesulfonyl chloride(28.5 mg, 0.15 mmol) and benzene (0.5 mL). A solution of 8 (73.3 mg,0.15 mmol) in dry benzene (2 mL) was added to this clear solution. Afterstirring for 15 minutes, triethylamine (13.9 μl, 0.10 mmol) was added.TLC and IR indicated the presence of a new “anhydride” species although8 was still present. Over a two hour period, additional triethylamine(47 μl) was added in an attempt to drive the reaction toward anhydrideand ketene formation. The reaction mixture was then heated to gentlereflux for several hours and additional triethylamine (54 μl) was addedbefore the mixture stirred overnight at 25° C. The reaction mixture wasthen evaporated and purified by column chromatography (9:1 hexane/ethylacetate increased to 4:1 hexane/ethyl acetate) to yield 21.8 mg (15%) ofpure 10 as an oil. Identification of 10 was confirmed by the fact thatupon exposure of 10 to methanol, acid 8 and methyl ester 9 wereisolated. Compounds 8 and 9 had been previously fully characterized.R_(f) 0.42 (4:1 hexanes/ethyl acetate); IR 3063, 3030, 2972, 1833, 1728,1273, 701 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.80 (m, 4H), 7.30 (m, 36H),5.45 (d, 2H), 4.57 (d, 2H), 4.10 (m, 2H), 3.90 (d, 2H), 3.70 (d, 2H),1.16 (d, 6H).

Synthesis of 2-Benzoyloxy-3-phenyl-propionic Acid (11)

A 50 mL three-necked flask was charged with 3-phenyllactic acid (1.0 g,6.0 mmol) and dry CH₂Cl₂ (12 mL). To this white slurry was added benzoylchloride (1.04 mL, 9.0 mmol) and the mixture was cooled to 0° C.Triethylamine (0.8 mL, 6.0 mmol) was added and a light yellow solutionresulted. 4-Dimethylaminopyridine (367 mg, 3.0 mmol) was added and thereaction mixture was warmed to 25° C. and stirred for 3 hours. Thereaction mixture was concentrated on a rotary evaporator and ether,ethyl acetate, and water were added. The mixture was extracted withether (3×) and ethyl acetate, dried over MgSO₄, filtered and evaporated.Purification by silica gel chromatography (4:1 hexanes/ethyl acetateincreased to 1:1 hexanes/ethyl acetate) yielded 392 mg (24%) of 11 as awhite solid. R_(f) 0.15 (1:1 hexanes/ethyl acetate); mp 113° C.; IR(CDCl₃) 3564-2560 (broad acid), 3028, 2924, 1720 (broad), 1452, 1268,716 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ11.25 (s, 1H), 8.08 (d, J=7.2 Hz, 2H)7.45 (m, 8H), 5.56 (m, 1H), 3.38 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ175.5, 165.9, 149.9, 135.6, 133.4, 130.1, 129.7, 129.3, 128.9, 128.5,128.4, 127.1, 72.9, 37.2; HRMS (FAB): Calcd for (M+Li) C₁₆H₁₄O₄Li,277.1052; Found, 277.1065; EA Calcd for C₁₆H₁₄O₄: C, 71.10; H, 5.22;Found: C, 71.04; H, 5.24.

1,4-Dimethyl-5,8-dioxo-1,5,8,8a-tetrahydro-4H-naphthalene-4a-carboxylicacid methyl ester (12)

1.7 g (10 mmol) of 2,5-dihydroxymethylbenzoate was stirred with 0.9 g(11 mmol) of 2,3-hexadiene in 20 ml of benzene at 10° C. 4.62 g (20mmol) of Ag₂O was added to the reaction mixture. Cooling bath wasremoved and the reaction mixture was stirred overnight in darkness. Thereaction mixture was deluded with 100 ml of Et₂O, filtered through 1inch silica gel plug and concentrated to yield 2.3 g (93%) of 12 as anorange solid. ¹H NMR (300 MHz, C₆H₆): δ1.06 (m, 6H), 2.32 (m, 1H), 2.88(q, 1H), 3.24 (s, 3H), 3.64 (d, 1H),5.39 (s, 2H), 6.13 (q, 2H); ¹³C NMR(75 MHz, CDCl₃): δ17.2, 17.8, 30.1, 34.4, 53.3, 53.5, 63.1, 128.2,128.6, 141.8, 142.5, 171.5, 196.7, 198.1; IR (neat): 750.5, 918.8,1259.6, 1467.7, 1680.2, 1715.6, 1746.6, 3114.6 cm⁻¹; HRMS calculated forC₁₄H₁₆O₄+H⁺: 249.1127, found: 249.1131.

1,4-Dimethyl-5,8-dioxo-1,5,8,8a-tetrahydro-4H-naphthalene-4a-carboxylicacid methyl ester (13)

2.5 g (10 mmol) of 12 was dissolved in 20 ml of toluene. 1.25 g (11mmol) of DABCO was added and the reaction mixture was stirred for 14hours at room temperature. The reaction mixture was deluded with 100 mlof Et₂O, filtered through 1 inch silica gel plug and concentrated toyield 2.4 g (93%) of 13 as an orange solid. ¹H NMR (300 MHz, CDCl₃):δ0.96 (d, 3H, J=6.9 Hz), 1.16 (m, 3H), 2.88 (m, 1H), 3.24 (q, 1H), 3.64(s, 4H), 5.39 (dd, 1H), 5.64 (m, 1H), 6.58 (d, 1H), 6.80 (d, 1H); ¹³CNMR (75 MHz, CDCl₃): δ17.2, 17.8, 30.1, 34.4, 53.3, 53.5, 63.1, 128.2,128.6, 141.8, 142.5, 171.5, 196.7, 198.1; IR (neat): 750.4, 918.9,1259.7, 1467.7, 1680.1, 1715.4, 1746.7, 3114.5 cm⁻¹; HRMS calculated forC₁₄H₁₆O₄+H⁺: 249.112, found: 249.114.

1,4-Dimethyl-5,8-methano-9,10-dioxo-1,5,8,8a,9,9a10,10a-octahydro-4H-antracene-4a-carboxylicacid methyl ester (14)

0.5 g (2 mmol) of 13 was stirred with 1.3 g (20 mmol) of freshlydistilled cyclopentadiene in 20 ml of EtOH at room temperature for 10hours. The reaction mixture was concentrated on rotavap to yield. 57 g(91%) of 14 as a white solid. ¹H NMR (300 MHz, CDCl₃): δ0.86 (d, 3H,J=6.9 Hz), 1.03 (d, 3H, J=7.0 Hz), 1.37 (d, 1H), 1.45 (d, 1H), 2.08 (d,1H), 2.73 (m, 1H), 3.11 (m, 2H), 3.24 (m, 1H), 3.39 (s, 1H), 3.59 (s,4H), 5.32 (dd, 1H), 5.62 (m, 1H), 6.16 (m, 1H), 6.22 (m, 1H); ¹³C NMR(75 MHz, CDCl₃): δ17.85, 22.29, 30.49, 32.79, 49.12, 49.64, 49.83,50.38, 50.55, 52.49, 53.27, 67.45, 129.49, 131.46, 135.60, 137.74,169.77, 203.95, 208.66; IR (CDCl₃): 732.4, 914.9, 1214.9, 1247.3,1470.4, 1705.5, 1750.1, 2982.4 cm⁻¹; HRMS calculated for C₁₉H₂₂O₄+H⁺:315.159, found: 315.160.

9-Hydroxy-1,4-dimethyl-5,8-methano-10-oxo-1,5,8,8a,9,9a,10,10a-octahydro-4H-anthracene-4a-carboxylicacid methyl ester (15)

0.96 g (3 mmol) of 14 was dissolved in 5 ml of anhydrous THF and cooledto −78° C. 0.8 ml of LAH (1M, THF) was added. After 2 hours TLCindicated no 14 was left. The reaction mixture was quenched with 2 g ofsolid NH₄Cl and deluded with 50 ml of ether. The reaction mixture waswashed with 10% HCl, twice with water, dried over magnesium sulfate andconcentrated. Silica gel column (Hexanes:EtOAc, 4:1) yielded 0.62 g(65%) of 17. ¹H NMR (300 MHz, CDCl₃): δ0.82 (d, 3H, J=6.9 Hz), 1.23 (d,3H, J=7.0 Hz), 1.28 (m, 2H), 1.37 (d, 1H, J=8 Hz), 1.62 (br.s, 1H) 1.78(dd, 1H, J=8 Hz, J=3.1 Hz), 2.47 (br.m, 1H), 2.96 (m, 2H), 3.21 (s, 1H),3.44 (m, 1H), 3.59 (s, 3H), 4.88 (br.t, 1H, J=9.2), 5.38 (dd, 1H, J=7.1Hz, J=3.1 Hz), 5.61 (m, 1H), 6.08 (m, 1H), 6.21 (m, 1H); ¹³C NMR (75MHz, CDCl₃): δ17.55, 23.53, 34.67, 35.55, 40.24, 44.06, 45.65, 48.85,49.50, 51.63, 52.44, 71.86, 128.49, 133.42, 135.73, 137.28, 169.97,207.56; IR (CDCl₃): 732.4, 914.9, 1214.9, 1247.3, 1470.4, 1705.5,1750.1, 2982.4, 3544.3 cm⁻¹; HRMS calculated for C₁₉H₂₄O₄+H⁺: 323.1758,found: 323.1775.

9-Benzoyloxy-1,4-dimethyl-5,8-methano-10-oxo-1,5,8,8a,9,9a,10,10a-octahydro-4H-anthracene-4a-carboxylicacid methyl ester (16)

0.15 g (0.45 mmol) of 15 was dissolved in 9 ml of 1:1:1 mixture ofanhydrous CH₂Cl₂, triethylamine and anhydrous DMF. 0.2 ml of benzoylchloride was added followed by catalytic amount of DMAP (0.01 g). In 24hours the reaction mixture was quenched by pouring into 50 ml of 1:1mixture of water and ether. The organic layer was washed with water,twice with saturated solution of ammonium chloride and with NaHCO₃.Ether solution was dried over magnesium sulfate and concentrated. Silicagel column (Hexanes:EtOAc, 3:1) yielded 0.12 g (78%) of 16. ¹H NMR (300MHz, CDCl₃): δ0.82 (d, 3H, J=6.9 Hz), 1.13 (d, 3H, J=7.0 Hz), 1.23 (m,2H), 2.16 (d, 1H, J=2.8 Hz), 2.37 (br.m, 1H,), 2.86 (s, 1H), 3.01 (dd,1H, J=3.2 Hz, J=5 Hz), 3.11 (m, 1H), 3.35 (m, 1H), 3.42 (s, 1H), 3.61(s, 3H), 5.28 (dd, 1H, J=7.1 Hz, J=3.1 Hz), 5.61 (m, 1H), 6.12 (m, 1H),6.22 (t, 1H, J=9.2), 6.31 (m, 1H), 7.43-8.07 (m, 5H); ¹³C NMR (75 MHz,CDCl₃): δ17.44, 22.93, 34.30, 35.88, 40.80, 46.83, 48.84, 48.88, 51.50,52.74, 64.51, 75.83, 128.39, 128.65, 128.92, 129.66, 129.71, 130.19,132.86, 133.18, 133.58, 135.83, 137.33, 166.71, 169.97, 207.35; IR(neat): 732.4, 914.9, 1214.9, 1247.3, 1470.4, 1705.5, 1712.2, 1750.1,2982.4 cm⁻¹; HRMS calculated for C₂₆H₂₈O₅+H⁺: 421.1251, found: 421.1246.

9-Benzoyloxy-1,4-Dimethyl-6-hydroxy-5,8-methano-10-oxo-1,5,6,7,8,8a,9,9a10,10a-decahydro-4H-antracene-4a-carboxylicacid methyl ester (17) and9-Benzoyloxy-1,4-Dimethyl-7-hydroxy-5,8-methano-10-oxo-1,5,6,7,8,8a,9,9a,10,10a-decahydro-4H-antracene-4a-carboxylicacid methyl ester (18)

0.42 g (1 mmol) of 16 was dissolved in 20 ml of anhydrous THF. 1.5 ml ofBH₃*SMe₂ (2M, in THF, 3 eq.) was added to the solution at 0° C. Thereaction mixture was stirred for 2 hours at 0° C. until TLC indicatedthe complete consumption of 16. After that the reaction mixture wasdeluded with 10 ml of MeOH. 0.1 g of NaOAc was added to the solution asa solid. Finally, 2 ml of 30% H₂O₂ was added. After two hours thereaction mixture was filtered through 1 inch silica gel plug, dried overmagnesium sulfate and concentrated. Silica gel column yielded 0.44 g(82%) of 2:1 mixture of alcohols 17 and 18. 17: ¹H NMR (300 MHz, CDCl₃):δ0.96 (d, 3H, J=6.9 Hz), 1.13 (d, 3H, J=7.0 Hz), 1.22 (m, 2H), 1.57 (d,1H, J=9.1 Hz), 1.83 (m, 2H), 2.12 (m, 2H), 2.43 (br.m, 1H), 2.62 (m,1H), 2.86 (m, 1H), 3.04 (m, 1H), 3.15 (m, 1H), 3.61 (s, 3H), 3.78 (d,1H, J=3 Hz), 5.38 (dd, 1H, J=7.1 Hz, J=3.1 Hz), 5.61 (t, 1H, J=3.1 Hz),6.29 (t, 1H, J=9.4 Hz), 7.43-8.07 (m, 5H); ¹³C NMR (75 MHz, CDCl₃):δ17.68, 22.62, 34.28, 34.67, 40.41, 47.72, 48.47, 49.65, 50.84, 52.83,64.81, 75.35, 128.39, 128.65, 128.92, 129.66, 129.71, 130.19, 132.86,133.18, 133.58, 135.83, 137.33, 165.92, 169.17, 207.28; IR (CDCl₃):732.4, 914.9, 1214.9, 1247.3, 1470.4, 1705.5, 1712.2, 1750.1, 2982.4cm⁻¹; HRMS calculated for C₂₆H₃₀O₆+Li⁺: 445.2202, found: 445.2197. 18:¹H NMR (300 MHz, CDCl₃): δ0.94 (d, 3H, J=6.9 Hz), 1.15 (d, 3H, J=7.0Hz), 1.23 (m, 2H), 1.62 (d, 1H, J=9.1 Hz), 1.81 (m, 2H), 2.16 (m, 2H),2.43 (br.m, 1H), 2.62 (m, 1H), 2.86 (m, 1H), 3.04 (m, 1H), 3.18 (t, 1H,J=7.1 Hz), 3.61 (s, 3H), 4.38 (d, 1H, J=3 Hz), 5.28 (dd, 1H, J=7.1 Hz,J=3.1 Hz), 5.61 (m, 1H), 6.22 (t, 1H, J=9.4 Hz), 7.43-8.07 (m, 5H); ¹³CNMR (75 MHz, CDCl₃): δ17.44, 22.93, 34.30, 35.88, 40.80, 46.83, 48.84,48.88, 51.50, 52.74, 64.51, 75.83, 128.39, 128.65, 128.92, 129.66,129.71, 130.19, 132.86, 133.18, 133.58, 135.83, 137.33, 166.71, 169.97,207.35; IR (CDCl₃): 732.4, 914.9, 1214.9, 1247.3, 1470.4, 1705.5,1712.2, 1750.1, 2982.4 cm⁻¹; HRMS calculated for C₂₆H₃₀O₆+Li⁺: 445.2202,found: 445.2197.

9-Benzoyloxy-1,4-Dimethyl-5,8-methano-6,10-dioxo-1,5,6,7,8,8a,9,9a10,10a-decahydro-4H-antracene-4a-carboxylicacid methyl ester (19)

0.44 g (1 mmol) of 17 was dissolved in 10 ml of dicloromethane and 0.22g (1.1 eq) of PCC was added. After stirring for 6 hours at roomtemperature TLC indicated that no 17 was left. The reaction mixture wasfiltered through 1 inch silica gel plug, dried over magnesium sulfateand concentrated. Silica gel gravity column (Hexanes:EtOAc, 4:1) yielded0.36 g (68%) of 19 as a white foam. ¹H NMR (300 MHz, CDCl₃): δ0.84 (d,3H, J=6.9 Hz), 1.15 (d, 3H, J=7.0 Hz), 1.23 (m, 2H), 1.62 (d, 1H, J=9.1Hz), 2.16 (m, 3H), 2.43 (br.m, 2H), 2.62 (m, 1H), 3.09 (m, 4H), 3.42 (t,1H, J=7.1 Hz), 3.61 (s, 3H), 5.28 (dd, 1H, J=7.1 Hz, J=3.1 Hz), 5.61 (m,1H), 6.32 (t, 1H, J=9.8 Hz), 7.43-8.07 (m, 5H); ¹³C NMR (75 MHz, CDCl₃):δ17.58, 22.93, 34.16, 36.32, 39.73, 40.86, 47.83, 52.91, 54.76, 64.78,74.73, 128.75, 129.06, 129.71, 132.19, 133.86, 135.83, 147.33, 166.71,169.97, 203.35, 213.28; IR (CDCl₃): 732.4, 1064.1, 1111.3, 1274.9,1446.5.4, 1446.5, 1712.5, 1743.1, 2847.3, 2924.4 cm⁻¹; HRMS calculatedfor C₂₆H₂₈O₆+Li⁺: 445.2202, found: 445.2197.

9-Benzoyloxy-1,4-Dimethyl-6-hydroxy-5,8-methano-10-oxo-1,5,6,7,8,8a,9,9a,10,10a-decahydro-4H-antracene-4a-carboxylicadd methyl ester (20)

0.44 g (1 mmol) of 19 was dissolved in 20 ml of anhydrous toluene and1.1 ml of lithium tritertbutoxyaluminun hydride (1M, THF) was added at0° C. The reaction mixture was stirred for 20 hours then was quenchedwith 3 ml of saturated solution of ammonium chloride and deluded with 20ml of ether. The reaction mixture was washed with water, dried overmagnesium sulfate and concentrated. Preparative TLC yielded 0.41 g (86%)of 20 as colorless oil. ¹H NMR (300 MHz, CDCl₃): δ1.06 (d, 3H, J=6.9Hz), 1.17 (d, 3H, J=7.0 Hz), 1.44 (m, 2H), 1.89 (m, 1H), 2.08 (dd, 2H,J=3.0 Hz, J=5.2 Hz), 2.31 (m, 1H), 2.39 (dd, 1H, J=9.8 Hz, J=3.8 Hz),2.81 (m, 1H), 3.08 (m 2H), 3.18 (m, 1H), 3.58 (m, 1H), 3.71 (s, 3H),4.60 (m, 1H), 5.38 (m, 1H), 5.64 (m, 1H), 1H, J=9.8 Hz, J=3.8 Hz),7.34-8.08 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ19.14, 23.05, 34.34, 36.18,37.15, 37.46, 37.88, 40.44, 41.04, 46.73, 48.53, 52.44, 57.02, 78.10,80.97, 126.27, 128.38, 128.42, 128.54, 129.24, 129.60, 130.13, 132.63,133.01, 166.09, 171.05, 176.39, 205.66; IR (neat): 732.4, 1064.1,1111.3, 1274.9, 1446.4, 1446.5, 1712.5, 1743.1, 2847.3, 2924.4 cm⁻¹;HRMS calculated for C₂₆H₃₀O₆+Li³⁰ : 445.2202, found: 445.2197.

1,4-Dimethyl-7-hydroxy-5,8-methano-9,10-dioxo-1,5,6,7,8,8a,9,9a,10,10a-decahydro-4H-antracene-4a-carboxylicadd methyl ester (21),1,4-Dimethyl-6-hydroxy-5,8-methano-9,10-dioxo-1,5,6,7,8,8a,9,9a,10,10a-decahydro-4H-antracene-4a-carboxylicacid methyl ester (22) and1,4-Dimethyl-5,8-methano-9,10-dioxo-1,5,6,7,8,8a,9,9a,10,10a-decahydro-4H-antracene-4a-carboxylicacid methyl ester (23)

I. Catalytic Hydroboration

0.48 g (1.5 mmol) of 20 was dissolved in 20 ml of anhydrous THF. 0.01 gof Wilkinson's catalyst was added to the solution at 0° C. After 20 min.0.25 ml of H₃*SMe₂ (2M, in THF) was added dropwise. Cooling bath wasremoved and the reaction mixture was stirred at 23° C. overnight. After24 hours the reaction mixture was deluded with 10 ml of MeOH. 2.5 ml ofNaOH (3N) was added followed by 0.35 ml of 30% H₂O₂. After additionalhour the reaction mixture was filtered through 1 inch silica gel plug,dried over magnesium sulfate and concentrated. Silica gel column yielded0.37 g (70%) of 20 and 0.09 g (18%) of 2:1 mixture of alcohols 21 and22.

II. Hydroboration with excess of BH₃*SMe₂

0.48 g (1.5 mmol) of 20 was dissolved in 20 ml of anhydrous THF at 0° C.2.25 ml of BH₃*SMe₂ (2M, in THF, 3 eq.) was added to the solution.Reaction was stirred for 2 hours at 0° C. until TLC indicated thecomplete consumption of 20. After that the reaction mixture was deludedwith 10 ml of MeOH. 2.5 ml of NaOH (3N) was added followed by 3 ml of30% H₂O₂. After additional hour the reaction mixture was filteredthrough 1 inch silica gel plug, dried over magnesium sulfate andconcentrated. Silica gel column yielded 0.44 g (82%) of 2:1 mixture ofalcohols 21 and 22 and 0.04 g (7%) of 23. 21: ¹H NMR (300 MHz, CDCl₃):δ0.86 (d, 3H, J=6.9 Hz), 1.15 (d, 3H, J=7.0 Hz), 1.37 (m, 2H), 1.77 (m,1H), 2.08 (d, 2H), 2.73 (m, 1H), 2.79 (m, 3H), 2.91 (m, 1H), 3.08 (m,1H), 3.18 (q, 1H), 3.59 (s, 3H), 3.79 (d, 1H), 5.38 (m, 1H), 5.69 (m,1H); ¹³C NMR (75 MHz, CDCl₃): δ17.85, 23.29, 30.49, 32.79, 34.15, 37.55,42.55, 49.12, 49.64, 50.38, 52.49, 53.27, 67.45, 69.55, 128.49, 131.46,169.77, 203.95, 208.66; IR (CDCl₃): 744.4, 918.9, 1213.9, 1280.3,1376.4, 1464.1, 1700.5, 1727.1, 2923.4 cm⁻¹; HRMS calculated forC₁₉H₂₂O₄+Li⁺: 339.1784, found: 339.1780. 22: ¹H NMR (300 MHz, CDCl₃):δ0.88 (d, 3H, J=6.9 Hz), 1.11 (d, 3H, J=7.0 Hz), 1.33 (m, 2H), 1.79 (m,1H), 2.08 (d, 2H), 2.71 (m, 1H), 2.79 (m, 3H), 2.93 (m, 1H), 3.08 (m,1H), 3.18 (q, 1H), 3.59 (s, 3H), 3.72 (d, 1H, J=3.2 Hz), 5.38 (m, 1H),5.69 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ17.85, 23.24, 30.43, 32.79,34.15, 37.54, 42.55, 49.22, 49.64, 50.38, 52.49, 53.27, 66.45, 69.32,128.45, 131.43, 169.77, 203.91, 208.71; IR (CDCl₃): 744.4, 918.9,1213.9, 1280.3, 1376.4, 1464.1, 1700.5, 1727.1, 2923.4 cm⁻¹; HRMScalculated for C₁₉H₂₂O₄+Li⁺: 339.1784, found: 339.1780. 23: ¹H NMR (300MHz, CDCl₃): δ0.96 (d, 3H, J=6.9 Hz), 1.13 (d, 3H, J=7.0 Hz), 1.21-1.57(m, 4H), 2.22 (d, 1H), 2.73-3.08 (m, 4H), 3.22 (m, 1H), 3.57 (s, 3H),5.38 (dd, 1H), 5.68 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ17.93, 22.57,24.67, 25.04, 30.77, 32.68, 39.01, 42.40, 43.49, 49.58, 50.23, 50.99,52.48, 53.08, 67.90, 129.17, 131.53, 169.52, 205.07, 209.43; IR (neat):733.8, 914.3, 1216.5, 1248.1, 1460.2, 1703.8, 1739.8, 2971.4 cm⁻¹; HRMScalculated for C₁₉H₂₄O₄+H⁺: 317.1753, found: 317.1741.

1,4-Dimethyl-5,8-methano-7,9,10-trioxo-1,5,6,7,8,8a,9,9a,10,10a-decahydro-4H-antracene-4a-carboxylicacid methyl ester (24)

0.16 g (0.5 mmol) of 22 was dissolved in 10 ml of dichloromethane and0.11 g (1.1 eq) of PCC was added. After stirring an for 6 hours at roomtemperature TLC indicated that no 21 was left. The reaction mixture wasfiltered through 1 inch silica gel plug, dried over magnesium sulfateand concentrated. Silica gel column (Hexanes:EtOAc, 4:1) yielded 0.12 g(73%) of 24 as a white foam. ¹H NMR (300 MHz, CDCl₃): δ0.82 (d, 3H,J=6.9 Hz), 1.12 (d, 3H, J=7.0 Hz), 1.77 (m, 2H) 1.85 (m, 2H), 2.05 (m,2H), 2.76 (m, 1H), 3.11 (m, 3H), 3.32 (m, 1H), 3.58 (s, 3H), 5.38 (m,1H), 5.69 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ17.68, 22.32, 30.75, 31.48,32.46, 37.78, 41.43, 42.19, 49.68, 51.33, 53.26, 54.36, 67.47, 129.16,130.92, 169.41, 200.71, 207.71, 212.73; IR (CDCl₃): 732.8, 915.6,1075.0, 1154.7, 1220.3, 1248.4, 1464.1, 1712.5, 1750.0, 2954.7 cm⁻¹;HRMS calculated for C₁₉H₂₂O₄+Li⁺: 337.1627, found: 337.1622.

1,4-Dimethyl-5,8-methano-6,9,10-trioxo-1,5,6,7,8,8a,9,9a,10,10a-decahydro-4H-antracene-4a-carboxylicadd methyl ester (25)

A solution of 85 mg (1.1 mmol) of freshly dried DMSO in 1 ml ofanhydrous CH₂Cl₂ was added to a solution of 70 mg (0.55 mmol) of oxalylchloride in 1.2 ml of anhydrous CH₂C₂, stirred and cooled to −78° C.After stirring an additional 5 min., a solution of 0.16 g (0.5 mmol) of22 dissolved in 1 iA of was anhydrous CH₂Cl₂ added dropwise over 10 min.After stirring an additional 15 min. at −78° C., the reaction mixturewas warmed up to −10° C. and 0.35 ml (2.5 mmol) of dried Et₃N was addeddropwise over 30 min. Finally, cooling bath was removed and the reactionmixture was warmed up to room temperature. After 45 min. 100 ml of EtOAcwas added followed by 20 ml of water. Organic layer was separated, driedover magnesium sulfate and concentrated. Silica gel column(Hexanes:EtOAc, 4:1) yielded 0.12 g (73%) of 27 as a white foam. ¹H NMR(300 MHz, CDCl₃): δ0.92 (d, 3H, J=6.9 Hz), 1.07 (d, 3H, J=7.0 Hz), 1.77(m, 1H), 1.85 (m, 2H), 2.08 (m, 2H), 2.76 (m, 1H), 3.08 (m, 3H), 3.32(q, 2H), 3.59 (s, 3H), 5.38 (dd, 1H), 5.69 (m, 1H); ¹³C NMR (75 MHz,CDCl₃): δ17.81, 21.98, 30.42, 32.47, 37.96, 40.69, 42.95, 49.15, 49.27,50.50, 53.33, 67.45, 56.75, 68.03, 128.91, 131.16, 169.31, 204.11,205.08, 212.63; IR (neat): 732.8, 915.6, 1075.0, 1154.7, 1220.3, 1248.4,1464.1, 1712.5, 1750.0, 2954.7 cm⁻¹; HRMS calculated for C₁₉H₂₂O₄+Li⁺:337.1627, found: 337.1622.

1,4-Dimethyl-6-hydroxy-5,8-methano-9,10-dioxo-1,5,6,7,8,8a,9,9a,10,10a-decahydro-4H-antracene-4a-carboxylicacid methyl ester (26)

0.08 g of 25 (0.23 mmol) was dissolved in 5 ml of anhydrous THF and 0.25ml of DIBAL-H (1M, Hexanes) was added at 0° C. the reaction mixture wasstirred at room temperature for 20 hours then was quenched with 5 ml of10% HCl and deluded with 20 ml of ether. the reaction mixture was washedwith water, dried over magnesium sulfate and concentrated. PreparativeTLC yielded 0.041 g (50%) of 26 as colorless oil. ¹H NMR (300 MHz,CDCl₃): δ1.11 (m, 3H), 1.20 (m, 3H), 1.45 (m, 2H), 1.77 (m, 1H), 2.73(m, 1H), 2.91 (m 4 2H), 3.08 (m, 1H), 3.22 (m, 2H), 3.39 (d, 1H), 3.62(s, 3H), 4.42 (m, 1H), 5.42 (m, 1H), 5.72 (m, 1H); ¹³C NMR (75 MHz,CDCl₃): δ17.75, 23.29, 31.49, 32.79, 34.15, 37.55, 42.55, 48.12, 49.64,50.38, 52.49, 53.27, 67.45, 73.55, 128.49, 133.46, 169.77, 205.00,207.50; IR (neat): 744.4, 1100.9, 1228.3, 1249.6, 1382.4, 1461.9,1700.9, 1727.1, 2923.4 cm¹; HRMS calculated for C₁₉H₂₂O₄+H⁺: 333.1702,found: 333.1692.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

Although the present methods and compounds have been described withreference to specific details of certain embodiments thereof, it is notintended that such details should be regarded as limitations upon thescope of the invention except as and to the extent that they areincluded in the accompanying claims.

What is claimed is:
 1. A method for preparing a compound having thestructure VII:

wherein, R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)R₂₂,wherein each R₂₁ is, independently, branched or straight chain C₁-C₁₂alkyl; and R₂₂ is substituted or unsubstituted aryl, aralkyl or fromC₁-C₁₂ branched or straight chain alkyl; R₁₇ is substituted orunsubstituted aryl, aralkyl, or from C₁-C₁₂ branched or straight chainalkyl; R₁₈ is branched or straight chain C₁-C₁₂ alkyl; unsubstituted orsubstituted aryl; aralkyl; Si(R₂₈)₃ or C(O)R₂₉, wherein, each R₂₈ is,independently, branched or straight chain C₁-C₁₂ alkyl; or aralkyl; R₂₉is substituted or unsubstituted aryl, aralkyl or from C₁-C₁₂ branched orstraight chain alkyl; R₁₉ and R₂₀ are, independently, branched orstraight chain C₁-C₁₂ alkyl, aryl, aralkyl, or C(O)OR₃₀; R₃₀ is branchedor straight chain C₁-C₁₂ alkyl; and V and W are, independently, sulfur,oxygen, or NR₄₃, wherein R₄₃ is hydrogen; branched or straight chainC₁-C₁₂ alkyl; or aralkyl, comprising, (a) admixing (i) a compound havingthe structure X

wherein R₁₈-R₂₀ are as above, (ii) a Lewis acid; and (iii) a base, toproduce a first intermediate; (b) reacting the first intermediate ofstep (a) with a compound having the structure XI:

wherein R₁₅ and R₁₇ are as above, to produce a second intermediate; and(c) admixing the second intermediate of step (b) with a proton source.2. The method of claim 1, wherein the base comprises an amide, asecondary amine or a tertiary amine.
 3. The method of claim 1, wherein acompound having the structure X is admixed with the Lewis acid prior toadmixing the base.
 4. The method of claim 1, wherein the Lewis acidcomprises stannous triflate, stannic chloride, stannous chloride,dialkylboron triflate, or titanium tetrachloride.
 5. The method of claim1, wherein R₁₅ is C(O)Ph.
 6. A compound having the structure VII:

wherein, R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)R₂₂,wherein each R₂₁ is, independently, branched or straight chain C₁-C₁₂alkyl; and R₂₂ is substituted or unsubstituted aryl, aralkyl or fromC₁-C₁₂ branched or straight chain alkyl; R₁₇ is substituted orunsubstituted aryl, aralkyl, or from C₁-C₁₂ branched or straight chainalkyl; R₁₈ is hydrogen; branched or straight chain C₁-C₁₂ alkyl;unsubstituted or substituted aryl; aralkyl; Si(R₂₈)₃ or C(O)R₂₉,wherein, each R₂₈ is, independently, branched or straight chain C₁-C₁₂alkyl; or aralkyl; R₂₉ is substituted or unsubstituted aryl, aralkyl orfrom C₁-C₁₂ branched or straight chain alkyl; R₁₉ and R₂₀ are,independently, branched or straight chain C₁-C₁₂ alkyl, aryl, aralkyl,or C(O)OR₃₀; R₃₀ is branched or straight chain C₁-C₁₂ alkyl; and V and Ware, independently, sulfur, oxygen, or NR₄₃, wherein R₄₃ is hydrogen;branched or straight chain C₁-C₁₂ alkyl; or aralkyl.
 7. The compound ofclaim 6, wherein V and W are sulfur.
 8. The compound of claim 6, whereinR₁₇ is phenyl and R₁₈ is benzoyl.
 9. The compound of claim 6, whereinR₁₈ is hydrogen.
 10. The compound of claim 6, wherein R₁₆ is C(O)Ph. 11.The compound of claim 6, wherein R₁₆ is C(O)Ph and R₁₈ is hydrogen. 12.A method for preparing a compound having the structure VII:

wherein, R₁₅ and R₁₆ are, independently, hydrogen, Si(R₂₁)₃ or C(O)OMe,wherein each R₂₁ is, independently, branched or straight chain C₁-C₁₂alkyl; and R₂₂ is substituted or unsubstituted aryl, aralkyl or fromC₁-C₁₂ branched or straight chain alkyl; R₁₇ is substituted orunsubstituted aryl, aralkyl, or from C₁-C₁₂ branched or straight chainalkyl; R₁₈ is hydrogen: R₁₉ and R₂₀ are, independently, branched orstraight chain C₁-C₁₂ alkyl, aryl, aralkyl, or C(O)OR₃₀; R₃₀ is branchedor straight chain C₁-C₁₂ alkyl; and V and W are, independently, sulfur,oxygen, or NR₄₃, wherein R₄₃ is hydrogen; branched or straight chainC₁-C₁₂ alkyl; or aralkyl, comprising, (a) admixing (i) a compound havingthe structure XIII

wherein R₁₉-R₂₀ and R₂₂ are as above, (ii) a Lewis acid; and (iii) afirst base, to produce a first intermediate; (b) reacting the firstintermediate of step (a) with a compound having the structure XI:

wherein R₁₅ and R₁₇ are as above, to produce a second intermediate; and(c) admixing the second intermediate with a basic buffer, wherein thebuffer comprises a second base.
 13. The method of claim 12, wherein thefirst base comprises an amide, a secondary amine or a tertiary amine.14. The method of claim 12, wherein the compound having the structureXIII and the Lewis acid are admixed prior to admixing the base.
 15. Themethod of claim 12, wherein the Lewis acid comprises stannous triflate,stannic chloride, dialkylboron triflate, or titanium tetrachloride. 16.The method of claim 12, wherein the second base comprises NaHCO₃ or aphosphate.